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DRUG METABOLISM REVIEWS
Vol. 36, No. 1, pp. 105–156, 2004
QSAR of Cytochrome P450
Corwin Hansch,* Suresh Babu Mekapati, Alka Kurup,and Rajeshwar Prasad Verma
Department of Chemistry, Pomona College, Claremont, California, USA
Key Words: QSAR; Cytochrome P450; ADME.
The cytochrome P450 class of enzymes is an extremely important and complex
group. It has a significant place in ADME (adsorption, distribution, metabolism,
elimination) that those developing new drugs must be concerned with. While there are
various ways in which organic compounds can undergo metabolic attack, P450 is
probably the most important. Recently, Lewis (2000) reviewed his extensive studies on
P450 and efforts to use QSAR to gain a deeper understanding on this important class of
enzymes. We have also been interested in the QSAR of P450 enzymes, but much has
appeared since our last review (Hansch and Zhang, 1993).
INDUCTION OF CYTOCHROME P450
The induction of P450 enzymes by various chemicals has received very little
attention, despite its great importance. In fact, the work by our group is all that we
could find.
*Correspondence: Corwin Hansch, Department of Chemistry, Pomona College, Claremont, CA,
91711, USA; E-mail: [email protected].
105
DOI: 10.1081/DMR-120028428 0360-2532 (Print); 1097-9883 (Online)
Copyright D 2004 by Marcel Dekker, Inc. www.dekker.com
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ORDER REPRINTS
The following examples illustrate what is known about P450 induction. Induction
in examples 1–3 is related to the hydrophobic properties of the chemicals.
1. Induction of P450 in chick hepatocytes by I (Sinclair et al., 1986) (Table 1).
log 1=C ¼ 0:85ð�0:21Þ log P þ 1:93ð�0:38Þ ð1Þ
n = 8, r2 = 0.942, s = 0.305, q2 = 0.897
2. Induction of P450 in chick hepatocytes by alcohols (Sinclair et al., 1986)
(Table 2)
log 1=C ¼ 0:78ð�0:14Þ log P þ 1:46ð�0:13Þ ð2Þ
n = 7, r2 = 0.976, s = 0.095, q2 = 0.954
Table 1. Induction of P450.
Log1/C PRED DEV logP
1 NHCOMe 1.90 1.60 0.30 �0.38
2 H 1.70 2.15 �0.45 0.26
3 NO2 2.82 2.43 0.39 0.59
4 OCH2CH3 2.48 2.61 �0.13 0.80
5 Me 2.61 2.75 �0.14 0.96
6 I 3.25 3.38 �0.13 1.70
7 (CH2)4CH3 4.70 4.46 0.24 2.96
8 (CH2)5CH3 4.81 4.88 �0.07 3.46
Table 2. Alcohols induction of P450.
Log1/C PRED DEV logP
1 Ethanol 1.30 1.22 0.08 � 0.31
2 Propanol 1.55 1.66 � 0.011 0.25
3 Isopropanol 1.49 1.50 � 0.01 0.05
4 Butanol 2.26 2.15 0.11 0.88
5 Isobutanol 2.02 2.11 � 0.09 0.83
6 Pentanol 2.64 2.68 � 0.04 1.56
7 Isopentanol 2.64 2.57 0.07 1.42
106 Hansch et al.
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ORDER REPRINTS
3. Induction of P450 in chick hepatocytes by 5,5-substituted barbiturates (Hansch
et al., 1990) (Table 3)
log 1=C ¼ 1:01ð�0:16Þ log P þ 2:77ð�1:27Þ ð3Þ
n = 9, r2 = 0.969, s = 0.183, q2 = 0.951
These results lead one to wonder if hydrophobic drugs could promote their
own destruction.
OXIDATION REACTIONS OF P450
1. Oxidation of ROH by P450 isozyme 3A from rat liver (Table 4). Data from
Morgan et al. (1982).
log 1=Km ¼ 0:56ð�0:24Þ log P þ 1:91ð�0:15Þ ð4Þ
n = 4, r2 = 0.981, s = 0.068, q2 = 0.903
2. Oxidation of X–C6H4SOMe by cytochrome P450 from rabbit liver micro-
somes (Table 5). Data from Watanabe et al., (1982a).
log Vmax ¼ �0:20ð�0:09Þsþ þ 0:36ð�0:04Þ ð5Þ
n = 4, r2 = 0.980, s = 0.014, q2 = 0.837
Table 3. Barbiturates induction of P450.
Log1/C PRED DEV logP
1 Dimethyl 2.28 2.33 � 0.05 � 0.43
2 Barbital 3.30 3.42 � 0.12 0.65
3 Probarbital 3.65 3.68 � 0.03 0.91
4 Phenobarbital 4.32 4.25 0.07 1.47
5 Butethal 4.64 4.67 � 0.03 1.89
6 Ethyl, Benzyl 4.71 4.86 � 0.15 2.07
7 Butabarbital 4.77 4.43 0.34 1.65
8 Pentobarbital 5.0 4.82 0.18 2.03
9 Ethyl, Hexyl 5.40 5.60 � 0.20 2.81
Table 4. Oxidation of ROH by P450.
Log1/Km PRED DEV MlogP
1 Me 1.46 1.48 � 0.02 � 0.77
2 C2H5 1.72 1.74 � 0.02 � 0.31
3 C3H7 2.13 2.05 0.08 0.25
4 C4H9 2.36 2.40 � 0.05 0.88
QSAR of Cytochrome P450 107
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ORDER REPRINTS
3. Hydroxylation of X–C6 H4CH3 by cytochrome P450 LM2 from rabbit liver
(Table 6). Data from Blake and Coon (1981).
log kcat=Km ¼ 0:99ð�0:21ÞC log P � 0:38ð�0:31ÞB14 � 0:41ð�0:64Þ ð6Þ
n = 11, r2 = 0.937, s = 0.152, q2 = 0.819
4. Oxidation of X–C6H4SMe to X–C6H4SOMe by cytochrome P450 from
phenobarbital-treated rabbit liver microsomes (Table 7). Data from Watanabe
et al. (1980).
log Vmax=Km ¼ �0:32ð�0:27ÞC log P þ 0:37ð�0:79Þ ð7Þ
n = 4, r2 = 0.930, s = 0.050, q2 = 0.700, outlier: H
5. Microsomal P450 oxidation using O2/NADPH for isotope effect (Table 8).
Data from Dinnocenzo et al. (1993).
X–C6H4N(HD2)2
log KH=Kd ¼ 0:12ð�0:05Þsþ þ 0:40ð�0:04Þ ð8Þ
n = 4, r2 = 0.982, s = 0.012, q2 = 0.982
Table 5. Oxidation of X–C6H4SOCH3 by P450.
LogVmax PRED DEV S+
1 4-OMe 0.51 0.51 � 0.01 � 0.78
2 4-Me 0.43 0.42 0.01 � 0.31
3 H 0.36 0.36 0.01 0.0
4 4-Cl 0.32 0.33 � 0.01 0.11
Table 6. Hydroxylation of X–C6H4CH3 by P450 LM2.
logkcat PRED DEV ClogP B1�4
1* 4-Me 2.51 2.13 0.38 3.14 1.52
2 4-F 1.94 1.84 0.09 2.78 1.35
3 4-Cl 2.30 2.24 0.06 3.35 1.80
4 4-Br 2.42 2.33 0.09 3.50 1.95
5 4-CN 0.76 1.04 � 0.28 2.07 1.60
6* 4-NO2 0.60 1.31 � 0.72 2.38 1.70
7 H 1.76 1.83 � 0.08 2.64 1.0
8 3-Me 2.33 2.33 0.0 3.14 1.0
9 3-F 1.98 1.98 0.0 2.78 1.0
10 3-Cl 2.54 2.54 0.0 3.35 1.0
11 3-Br 2.51 2.69 � 0.19 3.50 1.0
12 3-CN 1.45 1.27 0.18 2.07 1.0
13 3-NO2 1.70 1.58 0.12 2.38 1.0
*Outliers.
108 Hansch et al.
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ORDER REPRINTS
6. X–C6H4N(Me)CD3 (Table 9). Data from Dinnocenzo et al. (1993).
log KH=Kd ¼ �0:23ð�0:02Þs� þ 0:26ð�0:02Þ ð9Þ
n = 4, r2 = 0.999, s = 0.010, q2 = 0.997
7. Dehalogenation of 4-halo–2-F–C6H5NH2 by cytochrome P450 from rat liver
(Table 10). Data from Chubben et al. (1995).
log Vmax ¼ �1:25ð�0:70ÞC log P þ 2:28ð�1:37Þ ð10Þ
n = 5, r2 = 0.914, s = 0.223, q2 = 0.742
8. Hydroxylation rate of 4-X–C6H4CH3 by cytochrome P450 2B4 (Table 11).
Data from Lewis et al. (1995).
log kcat ¼ �0:77ð�0:54Þs þ 0:53ð�0:32ÞC log P � 0:67ð�1:0Þ ð11Þ
n = 7, r2 = 0.930, s = 0.134, q2 = 0.800 outlier: 4-CN
9. Oxidative cleavage of XCOOC2H5 by P450 2B4 (Table 12). Data from Peng
et al. (1995)
log 1=Km ¼ �0:87ð�0:36ÞC log P � 2:04ð�0:75Þ ð12Þ
n = 6, r2 = 0.920, s = 0.269 q2 = 0.911 outlier: C3H7
10. Oxidative cleavage of XCOOY by P450 (Table 13). Data from Peng et al.
(1995).
log Vmax=Km ¼ 1:60ð�0:45ÞC log P � 0:74ð�0:31ÞB5 � X
� 0:19ð�0:51Þ ð13Þ
n = 13, r2 = 0.908, s = 0.262, q2 = 0.816
outliers: X = Me, Y = C4H9; X = Me, Y = C5H11
Table 7. Oxidation of X–C6H4SCH3 by P450.
logVmax PRED DEV ClogP
1 4-OMe � 0.50 � 0.48 � 0.02 2.62
2 4-Me � 0.61 � 0.66 0.05 3.20
3* H � 0.87 � 0.50 � 0.36 2.70
4 4-Cl � 0.77 � 0.73 � 0.04 3.41
5 4-NO2 � 0.41 � 0.42 0.01 2.44
*Outlier.
Table 8. Oxidation of X–C6HN(CHD2)2 by P450.
log(KH) PRED DEV s�
1 H 0.40 0.40 0.0 0.0
2 Cl 0.43 0.42 0.01 0.19
3 CN 0.51 0.52 � 0.01 1.0
4 NO2 0.56 0.55 0.01 1.27
QSAR of Cytochrome P450 109
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ORDER REPRINTS
11. Oxidation of X–C6H4C CH to X–C6H4CH2COOH by P450 from rat liver
(Table 14). Data from Komives and Ortiz de Montellano (1987).
log Vmax ¼ �0:86ð�0:67Þsþ þ 0:62ð�0:29Þ ð14Þ
n = 4, r 2 = 0.939, s = 0.125, q2 = 0.855 outlier: X = 2-Me
12. Oxidation of 4-X–toluenes by cytochrome P450 LM2 (Table 15). Data from
White and McCarthy (1986).
log kcat=Km ¼ �0:63ð�0:57Þsþ þ 1:36ð�0:38ÞCMR
þ 2:26ð�1:38Þ ð15Þ
n = 7, r2 = 0.962, s = 0.146, q2 = 0.885 outlier: NO2
NO2 is much less active than predicted.
13. Demethylation of X–C6H4N(Me)2 by cytochrome P450 PB-B from rat liver
(Table 16). Data from MacDonald et al. (1989).
log kcat=Km ¼ 0:53ð�0:20ÞLog P þ 3:47ð�0:53Þ ð16Þ
n = 8, r2 = 0.879, s = 0.093, q2 = 0.823 outlier: 4-CHO
14. Oxidation of X–C6H4CH(CH3)OH by cytochrome P450 2B4 from rabbit
liver (Table 17). Data from Vaz and Coon (1994).
log kcat=Km ¼ 0:96ð�0:40ÞC log P � 0:99ð�0:68Þ ð17Þ
n = 7, r2 = 0.883, s = 0.191, q2 = 0.742 outlier: 4-NO2
As usual, NO2 is less active than predicted.
Table 9. Microsomal oxidation of X–C6H4N(Me)CD3 by P450.
log(KH) PRED DEV s�
1 H 0.26 0.26 0.0 0.0
2 Cl 0.30 0.30 0.0 0.19
3 CN 0.49 0.49 0.01 1.0
4 NO2 0.54 0.55 0.0 1.27
Table 10. Dehalogenation of 4-halo–2-F–C6H5NH2 by P450.
logVmax PRED DEV ClogP
1 H 0.79 0.72 0.08 1.26
2 4-F 0.48 0.43 0.04 1.49
3 4-Cl � 0.54 � 0.28 � 0.26 2.06
4 4-Br � 0.57 � 0.46 � 0.11 2.21
5 4-I � 0.54 � 0.79 0.25 2.47
110 Hansch et al.
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ORDER REPRINTS
15. Oxidation of X–C6H4CH(Me)OH by cytochrome P450-2E1 (Table 18). Data
from Vaz and Coon (1994).
log kcat=Km ¼ 0:95ð�0:24ÞC log P þ 0:19ð�0:17Þs� � 0:48 ð18Þ
n = 6, r2 = 0.982, s = 0.062, q2 = 0.899 outliers: 4-Me, 4-Br, 4-COOH
16. Oxidation of X–C6H4CH2OH by cytochrome P450-2B4 from rabbit liver
(Table 19). Data from Vaz and Coon (1994).
log kcat=Km ¼ 1:11ð�0:32ÞC log P þ 0:28ð�0:32Þsþ
� 1:44ð�0:45Þ ð19Þ
n = 7, r2 = 0.958, s = 0.143, q2 = 0.858 outlier: 4-F
17. Oxidation of X–C6H4CH2OH by cytochrome P450-2E1 from rat liver
(Table 20). Data from Vaz and Coon (1994).
log kcat=Km ¼ 0:67ð�0:18ÞC log P þ 0:19ð�0:14Þsþ
þ 0:09ð�0:22Þ ð20Þ
n = 7, r 2 = 0.966, s = 0.061, q2 = 0.918 outlier: 4-Br
Table 11. Hydroxylation of 4-X–C6H4CH3 by P450 2B4.
logKcat PRED DEV s ClogP
1 I 1.26 1.18 0.08 0.18 3.76
2 4-Me 1.11 1.12 � 0.01 � 0.17 3.14
3 4-Br 1.06 1.01 0.05 0.23 3.50
4 H 0.88 0.73 0.15 0.0 2.64
5 4-Cl 0.79 0.93 � 0.14 0.23 3.35
6 4-F 0.61 0.76 � 0.14 0.06 2.78
7* 4-CN 0.32 � 0.08 0.39 0.66 2.07
8 4-N02 0.01 � 0.01 0.02 0.78 2.38
*Outlier.
Table 12. Oxidative cleavage of X–COOC2H5 by P450 2B4.
logVmax PRED DEV ClogP
1 H � 1.04 � 1.02 � 0.02 0.27
2 Me � 0.41 � 0.59 0.18 0.71
3 C2H5 � 0.40 � 0.08 � 0.32 1.24
4* C3H7 � 0.49 0.43 � 0.93 1.77
5 C4H9 1.07 0.94 0.13 2.30
6 C5H11 1.73 1.45 0.28 2.83
7 C6H13 1.72 1.96 � 0.24 3.36
*Outlier.
QSAR of Cytochrome P450 111
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ORDER REPRINTS
18. Oxidation of X–C6H4CH2OH to yield 4-OH derivative by rat liver
microsome P450-NADPH/O2 (Table 21). Data from Chubben et al. (1994).
log 1=Km ¼ �1:59ð�0:26ÞC log P þ 3:37ð�0:45Þ ð21Þ
n = 14, r2 = 0.936, s = 0.163, q2 = 0.918
Adding an electronic term (HOMO or s�) makes a slight, dubious
improvement in QSAR 21.
19. O2 Consumption (nMole/Mg/min) of haloalkanes P450 (Table 22). Data from
Wang et al. (1993).
log k ¼ �0:15ð�0:05ÞC log P þ 0:43ð�0:09Þ ð22Þ
n = 6, r2 = 0.949, s = 0.018, q2 = 0.863
Table 13. Oxidative cleavage of XCOOY by P450.
X Y logVmax PRED DEV ClogP B5�X
1 H Me � 1.17 � 1.34 0.18 � 0.26 1.0
2 Me Me � 1.25 � 1.40 0.14 0.18 2.04
3 C2H5 Me � 1.46 � 1.38 � 0.08 0.71 3.17
4 C3H7 Me � 0.90 � 0.77 � 0.13 1.24 3.49
5 C4H9 Me � 1.12 � 0.70 � 0.43 1.77 4.54
6 H C2H5 � 0.57 � 0.50 � 0.08 0.27 1.0
7 Me C2H5 � 0.30 � 0.55 0.25 0.71 2.04
8 C2H5 C2H5 � 0.30 � 0.54 0.23 1.24 3.17
9 C3H7 C2H5 0.18 0.08 0.10 1.77 3.49
10 C4H9 C2H5 0.0 0.15 � 0.15 2.30 4.54
11 C5H11 C2H5 0.78 0.70 0.08 2.83 4.94
12 C6H13 C2H5 1.10 0.80 0.30 3.36 5.96
13 Me C3H7 � 0.12 0.30 � 0.42 1.24 2.04
14* Me C4H9 � 1.0 1.14 � 2.14 1.77 2.04
15* Me C5H11 � 1.0 1.99 � 2.99 2.30 2.04
*Outliers.
Table 14. Oxidation of X–C6H5C CH to X–C6H4COOH by P450.
logVmax PRED DEV s+
1 4-Me 0.88 0.88 � 0.01 � 0.31
2 H 0.74 0.62 0.12 0.0
3 4-Cl 0.40 0.52 � 0.13 0.11
4 4-NO2 � 0.05 � 0.06 0.01 0.79
5* 2-Me 1.15 0.88 0.26 � 0.31
*Outlier.
112 Hansch et al.
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ORDER REPRINTS
20. Defluorination of 2-Cl–1,1-di–F–ethane cytochrome P450 (Table 23). Data
from Wang et al. (1993).
log k ¼ 0:41ð�0:17ÞC log P � 0:51ð�0:32Þ ð23Þ
n = 6, r2 = 0.921, s = 0.063, q2 = 0.854
21. NADPH consumption of haloethanes by rabbit microsome P450 (Table 24).
Data from Wang et al., (1993).
log k ¼ 0:38ð�0:13ÞC log P þ 0:22ð�0:24Þ ð24Þ
n = 6, r2 = 0.948, s = 0.047, q2 = 0.905
22. 4-Hydroxylation of substituted anilines by rat liver P450 plus iodoso benzene
(Table 25). Data from Chubben et al. (1994).
log kcat=Km ¼ 3:48ð�0:79ÞHOMO þ 33:2ð�6:88Þ ð25Þ
n = 13, r2 = 0.896, s = 0.158, q2 = 0.863
In the case of QSAR 25, s� was just as satisfactory as HOMO.
Table 15. Hydroxylation of X–C6H4CH3 by P450 LM2.
LogKcat/Km PRED DEV s+ CMR
1 I 6.22 6.23 � 0.01 0.13 4.46
2 Me 5.25 5.36 � 0.11 � 0.31 3.62
3 Br 5.71 5.50 0.21 0.15 3.93
4 H 4.56 4.54 0.02 0.0 3.15
5 Cl 5.01 5.14 � 0.13 0.11 3.64
6 F 4.70 4.61 0.09 � 0.08 3.17
7 CN 4.71 4.78 � 0.07 0.66 3.63
8* NO2 4.14 4.88 � 0.74 0.79 3.76
*Outlier.
Table 16. Demethylation of X–C6H4N(Me)2 by P450 PB-B.
LogKcat/Km PRED DEV logP
1 3-Me 4.99 4.95 0.04 2.80
2 4-Me 4.90 4.95 � 0.05 2.81
3 H 4.62 4.69 � 0.07 2.31
4 4-F 5.06 4.87 0.19 2.65
5 4-Cl 5.10 5.17 � 0.07 3.22
6 4-Br 5.25 5.25 0.0 3.37
7* 4-CHO 4.06 4.43 � 0.37 1.81
8 4-CN 4.58 4.62 � 0.04 2.17
9 4-NO2 4.67 4.67 0.0 2.27
*Outlier.
QSAR of Cytochrome P450 113
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ORDER REPRINTS
23. Oxidation (dehalogenation) of 4-halogen–C6H4–NH2 by P450 supported by
(CH3)3CCOOH (Table 26). Data from Chubben et al. (1995).
log Vmax ¼ �5:71ð�2:1Þs þ 0:69ð�0:35Þ ð26Þ
n = 5, r2 = 0.962, s = 0.137, q2 = 0.892
24. Oxidation (dehalogenation) of 4-halogen–C6H4NH2 by P450 II B1 from rat
liver (Table 27). Data from Chubben et al. (1995).
log Vmax ¼ �0:95ð�2:1ÞC log P þ 0:81ð�0:38Þ ð27Þ
n = 5, r2 = 0.985, s = 0.076, q2 = 0.957
25. Metabolism of ROCONH2 to OH and ketone by rat hepatocytes (Table 28).
Data from Sargent et al. (1982).
log k ¼ 0:43ð�0:34ÞC log P þ 1:14ð�0:44Þ ð28Þ
n = 4, r2 = 0.937, s = 0.093, q2 = 0.786
It is likely that this is a P450 mediated reaction.
Table 17. Oxidation of X–C6H4CH(CH3)OH by P450 2B4.
LogKcat/Km PRED DEV ClogP
1 4-OMe 0.04 0.29 � 0.24 1.33
2 4-Me 0.78 0.85 � 0.06 1.91
3 H 0.51 0.37 0.14 1.41
4 4-F 0.55 0.50 0.04 1.56
5 4-Br 1.42 1.20 0.23 2.28
6 4-Cl 0.85 1.05 � 0.20 2.13
7 4-CN � 0.09 � 0.18 0.09 0.85
8* 4-NO2 � 0.36 0.12 � 0.48 1.16
*Outlier.
Table 18. Oxidation of X–C6H4CH(Me)OH by P450 2E1.
LogKcat/Km PRED DEV ClogP s
1 4-OMe 0.74 0.73 0.01 1.33 � 0.26
2* 4-Me 0.89 1.30 � 0.41 1.91 � 0.17
3 H 0.92 0.86 0.06 1.41 0.0
4 4-F 0.96 0.99 � 0.03 1.56 � 0.03
5* 4-Br 1.19 1.72 � 0.54 2.28 0.25
6 4-Cl 1.55 1.57 � 0.02 2.13 0.19
7* 4-COOH � 1.09 0.67 � 1.76 1.16 0.31
8 4-CN 0.45 0.51 � 0.06 0.85 1.0
9 4-NO2 0.91 0.86 0.05 1.16 1.27
*Outliers.
114 Hansch et al.
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ORDER REPRINTS
26. Oxidation (hydroxylation) of 4-X–toluenes by P450 2B4 (Table 29). Data
from Lewis et al. (1995).
log kcat ¼ 0:53ð�0:32ÞC log P � 0:77ð�0:54Þs � 0:67ð�1:0Þ ð29Þ
n = 7, r2 = 0.930, s = 0.134, q2 = 0.800 outlier: 4-CN
Another type of reaction that was studied with cytochrome P450 is
dealkylation that can be considered as an oxidation reaction.
27. Dealkylation of 4-X, 7-OMe coumarins by P450 206 expressed in human
lymphoblasts (Table 30). Data from Venhorst et al. (2000).
log Vmax=Km ¼ 0:46ð�0:23ÞL � X � 2:72ð�1:4Þ ð30Þ
n = 6, r2 = 0.886, s = 0.284, q2 = 0.751
It is of interest that hydrophobicity does not seem to play a role.
However, adding a term in log P does improve the correlation but not
enough to justify its use.
Table 19. Oxidation of X–C6H4CH2OH by P450 2B4.
LogKcat/Km PRED DEV s+ ClogP
1 4-OMe � 0.56 � 0.52 � 0.04 � 0.78 1.02
2 4-Me 0.38 0.26 0.12 � 0.31 1.60
3 H � 0.33 � 0.21 � 0.12 0.0 1.10
4* 4-F � 0.97 � 0.07 � 0.90 � 0.07 1.25
5 4-Br 0.80 0.79 0.01 0.15 1.97
6 4-Cl 0.60 0.61 � 0.01 0.11 1.82
7 4-CN � 0.48 � 0.66 0.18 0.66 0.54
8 4-NO2 � 0.42 � 0.28 � 0.14 0.79 0.85
*Outlier.
Table 20. Oxidation of X–C6H4CH2OH by P450 2E1.
LogKcat/Km PRED DEV s+ ClogP
1 4-OMe 0.62 0.63 0.0 � 0.78 1.02
2 4-Me 1.04 1.11 � 0.07 � 0.31 1.60
3 H 0.90 0.83 0.07 0.0 1.10
4 4-F 0.96 0.91 0.04 � 0.07 1.25
5* 4-Br 1.20 1.44 � 0.23 0.15 1.97
6 4-Cl 1.33 1.33 0.0 0.11 1.82
7 4-CN 0.52 0.58 � 0.05 0.66 0.54
8 4-NO2 0.83 0.81 0.02 0.79 0.85
*Outlier.
QSAR of Cytochrome P450 115
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ORDER REPRINTS
28. Human P450 1A2 expressed in insect cell using baculovirus. Data from
Venhorst et al. (2000). Same chemicals as QSAR 22, O–dealkylation of 4-X,
7-OMe coumarins (Table 31).
log Vmax=Km ¼ 0:30ð�0:11ÞL � X � 2:14ð�0:69Þ ð31Þ
n = 5, r2 = 0.960, s = 0.114, q2 = 0.828
L is a measure of substituent length. QSAR 30 and 31 are in
close agreement.
29. Cytochrome P450 from rabbit liver microsomes. Oxidation of X–C6H4SCH3
(Table 32). Data from Watanabe et al. (1982b).
log Vmax=Km ¼ �0:32ð�0:27ÞC log P þ 0:37ð�0:79Þ ð32Þ
n = 4, r2 = 0.930, s = 0.050, q2 = 0.720 outlier: X = H
Table 21. Oxidation of X–C6H4CH2OH by P450 NADPH/O2.
logKcat/Km PRED DEV ClogP
1 H 1.98 1.93 0.05 0.92
2 2-F 1.66 1.39 0.27 1.26
3 2-Cl 0.32 0.35 � 0.03 1.91
4 2-Br 0.05 0.03 0.02 2.11
5 2-I � 0.27 � 0.30 0.03 2.32
6 3-F 1.23 1.26 � 0.03 1.34
7 3-Cl 0.14 0.35 � 0.21 1.91
8 3-Br 0.19 0.11 0.08 2.06
9 3-I � 0.12 � 0.30 0.18 2.32
10 2,6-di–F 1.25 1.15 0.10 1.41
11 2,5-di–F 0.84 1.02 � 0.18 1.49
12 2,3-di–F 1.18 1.14 0.04 1.42
13 3,5-di–F 1.01 0.90 0.11 1.57
14 2,3,6-tri–F 0.46 0.88 � 0.42 1.57
15* 2,3,5,6-tetra–F � 0.92 0.64 � 1.56 1.72
*Outlier.
Table 22. O2 consumption of haloalkanes by P450 oxidation.
logK PRED DEV ClogP
1 CF3CHClBr 0.79 0.80 � 0.01 2.45
2 CF3CHCl2 0.79 0.78 0.02 2.31
3 CF3CH2Cl 0.69 0.69 0.0 1.71
4 CF3CHFCl 0.70 0.71 � 0.01 1.87
5 CF3CH2F 0.64 0.62 0.02 1.27
6 CF3CHF2 0.62 0.64 � 0.02 1.43
116 Hansch et al.
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ORDER REPRINTS
30. Inhibition of human cytochrome P450 1A2 by trans-stilbene analogs on
ethoxyresovutin O-deethylation (Table 33). Data from Kim et al. (2002).
log 1=C ¼ �5:17ð�1:93ÞMgVol þ 15ð�4:07Þ ð33Þ
n = 7, r2 = 0.904, s = 0.552, q2 = 0.749
outliers: 2,4-di–OMe–C6H3; 3,4,5-tri–OMe–C6H2; furanyl MgVol is the
volume of the chemical.
31. Inhibition of human cytochrome P450 1A1 by trans-stilbene analogues on
ethoxyresorutin O–deethylation (Table 34). Data from Kim et al. (2002).
log 1=C ¼ 0:03ð�0:01ÞNVE þ 2:78ð�1:36Þ ð34Þ
n = 8, r2 = 0.859, s = 0.194, q2 = 0.783
outliers: 4-pyridinyl; 2-thienyl
NVE is the sum of valence electrons and is a measure of polarizability.
32. Inhibition of binding of aminopyrine to P450 (Table 35). Data from Krainev
et al., (1985).
log k ¼ �0:70ð�0:40ÞC log P þ 1:68ð�1:2Þ ð35Þ
n = 5, r2 = 0.977, s = 0.301, q2 = 0.702
33. Inhibition of rat P450 by p-amino-diphenyl-ethers (Table 36). Data from Fu
et al. (1994)
log 1=C ¼ 1:10ð�0:48ÞC log P � 0:11ð�0:07ÞC log P2
� 3:92ð�0:83Þ ð36Þ
n = 16, r2 = 0.914, s = 0.106, q2 = 0.887
optimum Clog P = 5.24 (4.51–8.48) outlier: 2’-Me
Table 23. Defluorination of 2-Cl–1,1-di–F–ethane by P450.
logK PRED DEV ClogP
1 CF3CHClBr 0.49 0.49 0.0 2.45
2 CF3CHCl2 0.41 0.44 � 0.02 2.31
3 CF3CH2Cl 0.28 0.19 0.09 1.71
4 CF3CHFCl 0.25 0.26 � 0.01 1.87
5 CF3CH2F 0.03 0.01 0.02 1.27
6 CF3CHF2 � 0.01 0.07 � 0.08 1.43
Table 24. NADPH consumption of haloethanes in P450 oxidation.
logK PRED DEV ClogP
1 CF3CHClBr 1.14 1.16 � 0.02 2.45
2 CF3CHCl2 1.12 1.11 0.02 2.31
3 CF3CH2Cl 0.95 0.88 0.07 1.71
4 CF3CHFCl 0.91 0.94 � 0.03 1.87
5 CF3CH2F 0.71 0.71 0.0 1.27
6 CF3CHF2 0.73 0.77 � 0.04 1.43
QSAR of Cytochrome P450 117
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ORDER REPRINTS
34. Inhibition of aniline hydroxylation of cytochrome P450 by miscellaneous
alcohols (Table 37). Data from Lewis (1987).
log 1=C ¼ 0:45ð�0:21Þ log P þ 0:43ð�0:14ÞEs þ 3:29ð�0:34Þ ð37Þ
n = 16, r2 = 0.889, s = 0.146, q2 = 0.821
outliers: CH3OH; C2H5OH; 3-Me–butanol-1; 2-Me–3-pentanol; 2,4-di–Me–
3-pentanol; t-amyl alcohol
Es is the Taft steric parameter. Because all values are negative, the
positive coefficient with Es indicates a negative steric effect.
35. Inhibition of aniline hydroxylation of cytochrome P450 by alcohols
(Table 38). Data from Shusterman and Johnson (1990).
log 1=C ¼ 0:48ð�0:13Þ log P � 0:66ð�0:18ÞM � 0:33ð�0:16ÞA
� 0:57ð�0:18Þ ð38Þ
n = 20, r2 = 0.893, s = 0.190, q2 = 0.824 outliers: CH3OH; t–amyl alcohol
A is the number of side-chain carbons on primary and secondary
alcohols. M is the number of side chains on secondary alcohols, where O is
not bonded to C2.
Table 25. 4-Hydroxylation of X–Anilines by P450.
logKcat PRED DEV HOMO
1 H 3.51 3.47 0.04 � 8.52
2 2-F 2.93 3.02 � 0.09 � 8.65
3 2-Cl 3.27 3.13 0.14 � 8.62
4 2-Br 2.92 2.95 � 0.03 � 8.67
5 2-I 2.90 3.02 � 0.12 � 8.65
6 3-F 2.89 2.67 0.22 � 8.75
7 3-Cl 2.75 2.74 0.01 � 8.73
8 3-Br 2.44 2.64 � 0.20 � 8.76
9 3-I 2.68 2.64 0.04 � 8.76
10 2,6-di–F 2.71 2.46 0.25 � 8.81
11 2,5-di–F 2.14 2.39 � 0.25 � 8.83
12 2,3-di–F 2.06 2.15 � 0.09 � 8.90
13 2,3,6-tri–F 1.86 1.77 0.09 � 9.01
Table 26. Dehalogenation of 4-halo–C6H4 –NH2 by P450.
logVmax PRED DEV s
1 H 0.76 0.69 0.07 0.0
2 4-F 0.29 0.35 � 0.06 0.06
3 4-Cl � 0.46 � 0.63 0.17 0.23
4 4-Br � 0.68 � 0.63 � 0.05 0.23
5 4-I � 0.47 � 0.34 � 0.13 0.18
118 Hansch et al.
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ORDER REPRINTS
36. X–Cyclopropanes in activation of cytochrome P450 (Table 39). Data from
Guengerich et al. (1984).
log k ¼ �1:31ð�0:34ÞE 1
2þ 2:06ð�0:81Þ ð39Þ
n = 12, r2 = 0.880, s = 0.300, q2 = 0.826
outliers: 1-Me, 1-Br; 1-Br; 1-SC6H5
E1/2 is the oxidation potential.
37. Inhibition of P450 1B1 by trans-stilbene analogs (Table 40). Data from Kim
et al. (2002)
log 1=C ¼ 1:31ð�0:61ÞL � 2 þ 2:06ð�1:6Þ ð40Þ
n = 6, r2 = 0.900, s = 0.366, q2 = 0.806 outlier: 3,5-di–OMe–C6H3
L is substituent length.
38. Inhibition of rat liver P450 formation of GSSG from glutathione by 3,5-di–
X–4-OH acetanilide (Table 41). Data from Bessems et al. (1996).
log K ¼ 2:41ð�1:14ÞMgVol � 4:12ð�1:74Þ ð41Þ
n = 4, r2 = 0.952, s = 0.154, q2 = 0.591 outliers: 3,5-di–Me; 3,5-di–I
MgVol is compound volume.
39. Inhibition of P450 BM-3 from Bacillus megaterium by ROH (Table 42). Data
from Deller and Turner (1997).
log 1=C ¼ 0:57ð�0:15Þ log P � 0:12ð�0:08Þ log P2
þ 0:62ð�0:10Þ ð42Þ
n = 6, r2 = 0.991, s = 0.057, q2 = 0.949 optimum log P = 1.53 (2.3 to 8.4)
Table 27. Dehalogenation of 4-halo–C6H4 –NH2 by P450 IIB1.
logVmax PRED DEV ClogP
1 H � 0.01 � 0.06 0.05 0.92
2 4-F � 0.55 � 0.46 � 0.09 1.34
3 4-Cl � 0.92 � 1.0 0.08 1.91
4 4-Br � 1.15 � 1.14 � 0.02 2.06
5 4-I � 1.40 � 1.38 � 0.01 2.32
Table 28. Metabolism of ROCONH2 by P450.
LG1/KS PRED DEV logP
1 C4H9 2.72 2.75 � 0.03 0.85
2 C5H11 3.03 3.06 � 0.03 1.36
3 C6H13 3.30 3.36 � 0.06 1.85
4 C7H15 3.77 3.70 0.07 2.40
5 C8H17 4.15 3.97 0.18 2.85
6 C10H21 4.46 4.59 � 0.13 3.85
QSAR of Cytochrome P450 119
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ORDER REPRINTS
40. Inhibition of human testicular P450 by X–adamatane (Table 43). Data from
Chan et al. (1996).
log 1=C ¼ 1:60ð�0:33ÞC log P þ 1:47ð�0:41ÞI � 2
þ 1:23ð�1:1Þ ð43Þ
n = 11, r2 = 0.951, s = 0.288, q2 = 0.903
I - 2 = 1 for 4-pyridyl derivatives outlier: OCHMe(R)–4-pyridyl
41. Inhibition of P450 by ROH (Table 44). Data from LaBella et al. (1997).
log 1=Ki ¼ 0:94ð�0:10ÞC log P � 3:87ð�0:59Þbilin C log P
þ 1:25ð�0:21Þ ð44Þ
n = 26, r2 = 0.951, s = 0.258, q2 = 0.944 optimum Clog P = 4.42
outlier: C13H27OH
42. Inhibitory activity by 1-(X–C6H4), (3,4-imidazoyl–CH2)–C6H4 on rat
testicular P450 17 (Table 45). Data from Wachall et al. (1999).
log 1=C ¼ 0:62ð�0:16ÞI � 0:95ð�0:41ÞB1 � 3X
þ 0:72ð�0:39ÞB1 � 4X � 0:43ð�0:14ÞB5 � 4X
þ 5:78ð�0:81Þ ð45Þ
n = 23, r2 = 0.875, s = 0.162, q2 = 0.810 I = 1 for Y = 4-imidazolyl–Me
The steric parameters, B1, B5, and L as well as all other parameters are
discussed in Ref. (Hansch and Leo, 1996).
Table 29. Hydroxylation of 4-X–C6H4Me.
logKcat/vmax PRED DEV ClogP
1 C3H7 1.24 1.26 � 0.02 0.35
2 C4H9 1.62 1.54 0.08 0.88
3 C5H11 1.68 1.77 � 0.09 1.41
4 C6H13 1.97 1.93 0.04 1.94
5 C8H17 2.10 2.10 0.0 3.0
Table 30. Dealkylation of 4-X–7-OMe coumarins by P450 2O6.
logVmax/Km PRED DEV L � X
1 CH2NH2 � 0.61 � 0.86 0.25 4.02
2 CH2NHCH3 � 0.47 � 0.49 0.02 4.83
3 CH2NHC2H5 0.15 0.08 0.07 6.07
4 CH2NHC3H7 0.66 0.46 0.20 6.88
5 CH2NHC4H9 0.94 1.03 � 0.09 8.13
6 CH2N(CH3)2 � 0.94 � 0.49 � 0.45 4.83
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ORDER REPRINTS
43. Inhibitory activity of 1-(X–C6H4), (3,4-imidazoyl–CH2)–C6H4 on human
testicular P450 17 (Table 46). Data from Wachall et al. (1999).
log 1=C ¼ �0:47ð�0:16ÞC log P þ 0:55ð�0:19ÞI
� 0:67ð�0:30Þsþ � 0:55ð�0:19ÞB5 � 4X ð46Þ
n = 25, r2 = 0.885, s = 0.208, q2 = 0.822
I = 1 for imidazolyl derivatives outlier: X = 3-NH2, Y = 3-imidazoyl–CH2
The difference between QSAR 45 and 46 is striking, and of course, it
could have been expected.
44. Inhibition of human placental P450 AROM by compounds such as those in
QSAR 45 and 46 (Table 47). Data from Wachall et al. (1999)
log 1=C ¼ 0:58ð�0:27ÞC log P þ 4:23ð�0:95Þ ð47Þ
n = 7, r2 = 0.856, s = 0.174, q2 = 0.741 outliers: X = 4’-OH, 3’-OH
These simpler inhibitors yield a much simpler QSAR.
45. Inhibition of rat P450 17 by substituted biphenyl compounds (Table 48). Data
from (Zhuang et al.).
log 1=C ¼ �1:21ð�0:68ÞCMR þ 15:64ð�5:56Þ ð48Þ
n = 5, r2 = 0.915, s = 0.157, q2 = 0.797 outlier: OMe
46. Inhibition of human P450 17 by miscellaneous biphenyls (Table 49). Data
from (Zhuang et al.).
Table 31. Dealkylation of 4-X–7-OMe coumarins by P450 1A2.
logVmax/Km PRED DEV NVE
1 CH2NH2 � 1.04 � 0.97 � 0.07 78.0
2 CH2NHCH3 � 0.67 � 0.67 � 0.01 84.0
3 CH2NHC2H5 � 0.22 � 0.36 0.13 90.0
4 CH2NHC3H7 � 0.02 � 0.05 0.03 96.0
5 CH2NHC4H9 0.17 0.26 � 0.09 102.0
6* CH2N(CH3)2 0.07 � 0.36 0.43 90.0
*Outlier.
Table 32. P450 oxidation of X–C6H4SCH3.
logVmax/Km PRED DEV ClogP
1 4-OMe � 0.50 � 0.48 � 0.02 2.62
2 4-Me � 0.61 � 0.66 0.05 3.20
3* H � 0.87 � 0.50 � 0.36 2.70
4 4-Cl � 0.77 � 0.73 � 0.04 3.41
5 4-NO2 � 0.41 � 0.42 0.01 2.44
*Outlier.
QSAR of Cytochrome P450 121
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ORDER REPRINTS
log 1=C ¼ �1:27ð�0:79ÞMgVol þ 16:74ð�6:58Þ ð49Þ
n = 5, r2 = 0.897, s = 0.195, q2 = 0.758 outlier: F
CMR and MgVol are not highly collinear; hence, electronic effects are lacking.
47. Inhibition of rat testicular P450 17 by X–C6H4–C6H4CH2–imidazolyl
(Table 50). Data from Wachall et al. (1999).
log 1=C ¼ 0:62ð�0:16ÞI � Y � 0:95ð�0:41ÞB1 � 3X
þ 0:72ð�0:39ÞB1 � 4X � 0:43ð�0:12ÞB5 � 4X
þ 5:78ð�0:81Þ ð50Þ
n = 23, r2 = 0.875, s = 0.162, q2 = 0.810 I-Y = 1 for 4-CH2-imidazolyl
outlier: X = 3-OH, Y = 4-CH2–imidazolyl
48. Inhibition of human placental P450 by X–C6H4–C6H4CH2–imidazolyl
(Table 51). Data from Wachall et al. (1999).
Table 33. Inhibition of P450 1A2 by trans-stilbine analogs.
log1/C PRED DEV MgVol
1* 2,4-di–OMe–C6H3 5.51 3.78 1.72 2.36
2* 3,4,5-tri–OMe–C6H2 6.03 2.75 3.28 2.56
3 3,5-di–OMe–C6H3 3.70 3.78 � 0.08 2.36
4 3,4-di–OMe–C6H3 3.24 3.78 � 0.54 2.36
5 4-OMe–C6H4 5.21 4.82 0.39 2.16
6 2-OH–4-OMe–C6H3 4.51 4.51 � 0.01 2.22
7 2–F–4-OMe–C6H3 5.24 4.73 0.51 2.18
8 4-Pyridyl 6.54 7.30 � 0.76 1.68
9* 3-Furanyl 6.13 8.02 � 1.89 1.54
10 2-Thienyl 7.96 7.47 0.49 1.65
*Outliers.
Table 34. Inhibition of P450 1A1 by trans-silbene analogs.
log1/C PRED DEV NVE
1 2,4-di–OMe–C6H3 6.52 6.32 0.20 116.0
2 3,4,5-tri–OMe–C6H2 6.85 6.68 0.17 128.0
3 3,5-di–OMe–C6H3 6.04 6.32 � 0.28 116.0
4 3,4-di–OMe–C6H3 6.12 6.32 � 0.19 116.0
5 4-OMe–C6H4 6.08 5.95 0.13 104.0
6 2-OH–4-OMe–C6H3 6.01 6.14 � 0.13 110.0
7 2-F–4-OMe–C6H3 6.21 6.14 0.08 110.0
8* 4-Pyridyl 5.96 5.28 0.68 82.0
9 3-Furanyl 5.18 5.16 0.02 78.0
10* 2-Thienyl 7.22 5.16 2.06 78.0
*Outliers.
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log 1=C ¼ �0:47ð�0:16ÞC log P þ 0:55ð�0:19ÞI � Y
� 0:67ð�0:30Þsþ � 0:55ð�0:19ÞB5 � 4X
þ 7:91ð�0:53Þ ð51Þ
n = 25, r2 = 0.885, s = 0.208, q2 = 0.822
I � Y = 1 for 4-CH2-imidazolyl derivatives
outlier: X = 3-NH2, Y = 3-CH2-imidazolyl
49. Inhibition of mouse cytochrome P450 2A5 by miscellaneous chemicals
(Table 52). Data from Poso et al. (2001).
log 1=C ¼ 10:1ð�2:35ÞMgVol � 24:12ð�8:81Þbilin MgVol
� 4:14ð�1:57Þ ð52Þ
n = 28, r2 = 0.904, s = 0.441, q2 = 0.877 optimum MgVol = 1.52
Table 36. Inhibition of demethylation of aminopyrine by 4-NH2 –C6H4OC6H4 –X.
log1/C PRED DEV ClogP
1 2’,4’-di–Cl � 0.93 � 1.08 0.15 4.56
2 4’-Cl � 1.11 � 1.19 0.08 4.04
3 2’,3’,5’-tri–Cl � 1.04 � 1.04 0.0 5.17
4 3’-Cl � 1.28 � 1.19 � 0.09 4.04
5 2’-Cl � 1.16 � 1.25 0.09 3.81
6 H � 1.45 � 1.48 0.03 3.18
7 3’-Me � 1.44 � 1.29 � 0.15 3.68
8 4’-Me � 1.18 � 1.29 0.11 3.68
9 3’,4’-di–Me � 1.32 � 1.16 � 0.16 4.13
10* 2’-Me � 1.04 � 1.29 0.25 3.68
11 3’,5’-di–Me � 1.12 � 1.06 � 0.06 4.79
12 2’,3’-di–Me � 1.20 � 1.10 � 0.10 4.44
13 4’-Br � 1.01 � 1.15 0.14 4.19
14 4’-NO2 � 1.51 � 1.46 � 0.05 3.23
15 4’-NH2 � 2.09 � 2.13 0.04 2.01
16 2’-NH2 � 2.06 � 2.01 � 0.05 2.19
17 2’,6’-di–Me � 1.14 � 1.15 0.01 4.18
*Outlier.
Table 35. Inhibition of binding of aminopyrine to P450 by 1-naphthyl(CH2)X – S –
CH[PO(OH)2]2.
logK PRED DEV ClogP
1 (CH2)1 0.82 0.94 � 0.12 1.06
2 (CH2)3 0.35 0.37 � 0.02 1.89
3 (CH2)5 � 0.12 � 0.37 0.25 2.95
4 (CH2)6 � 0.49 � 0.74 0.25 3.48
5 (CH2)7 � 1.47 � 1.11 � 0.36 4.01
QSAR of Cytochrome P450 123
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50. Inhibition of human liver P450 2C8 by sulfaphenazoles expressed in yeast
microsomes (Table 53). Data from Ha-Duong et al. (2001).
log 1=C ¼ �0:74ð�0:65ÞsX þ 0:49ð�0:18ÞL � X
þ 0:38ð�0:01ÞL � Y þ 1:31ð�0:89Þ ð53Þ
n = 13, r2 = 0.924, s = 0.191, q2 = 0.759
outlier: X = CH2CH = CH2, Y = CH2C6H5
51. Inhibition of cytochrome P450 2C9 expressed in yeast microsomes by
sulfaphenazoles (Table 54). Data from Ha-Duong et al. (2001).
log 1=C ¼ �1:63ð�0:72ÞL � Y þ 1:68ð�1:0Þbilin L � Y
þ 9:26ð�1:67Þ ð54Þ
n = 13, r2 = 0.885, s = 0.321, q2 = 0.814
outliers: X = 3-NH2–C6H4, Y = H; X = NH2, Y = Me
QSAR 54 describes an inverted parabola. That is, activity at first
decreases with increasing value of L-Y but at the inversion point 4.59,
activity begins to increase. This is due to an allosteric effect in the receptor
Table 37. Inhibition of aniline hydroxylation by P450 of alcohols.
log1/C PRED DEV logP Es
1* Methanol � 0.09 2.41 � 2.50 � 0.77 � 1.24
2* Ethanol 1.90 2.58 � 0.68 � 0.31 � 1.31
3 Propanol 2.52 2.71 � 0.19 0.25 � 1.60
4 Butanol 2.95 2.97 � 0.02 0.88 � 1.63
5 Pentanol 3.27 3.27 0.0 1.56 � 1.64
6 Hexanol 3.54 3.48 0.06 2.03 � 1.64
7 Heptanol 3.68 3.79 � 0.11 2.72 � 1.64
8 2-Me–Propanol 2.61 2.69 � 0.08 0.76 � 2.17
9 1,2-Me–Butanol-1 2.85 2.89 � 0.04 1.22 � 2.17
10* 3-Me–Butanol-1 2.81 3.23 � 0.42 1.42 � 1.59
11 Neopentyl 2.33 2.58 � 0.25 1.31 � 2.98
12 Benzyl 3.32 3.08 0.24 1.10 � 1.62
13 2-Propanol 2.53 2.57 � 0.04 0.05 � 1.71
14 2-Butanol 2.65 2.53 0.12 0.61 � 2.37
15 2-Pentanol 2.93 2.79 0.14 1.19 � 2.37
16 2-Hexanol 3.15 3.04 0.11 1.76 � 2.37
17 2-Heptanol 3.25 3.29 � 0.04 2.31 � 2.37
18 3-Pentanol 2.63 2.43 0.20 1.21 � 3.22
19 3-Hexanol 2.53 2.63 � 0.10 1.65 � 3.22
20* 2-Me–3–Pentanol 2.11 3.97 � 1.86 1.53 0.0
21* 2,4-di–Me–3-Pentanol 1.62 4.15 � 2.53 1.93 0.0
22* T-Amyl 0.44 2.21 � 1.77 0.89 � 3.41
*Outliers.
124 Hansch et al.
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Table 38. Inhibition of aniline hydroxylation by P450 by alcohols.
log1/C PRED DEV logP M A
1* Methanol � 3.09 � 0.94 � 2.15 � 0.77 0.0 0.0
2 Ethanol � 1.10 � 0.71 � 0.39 � 0.31 0.0 0.0
3 Propanol � 0.48 � 0.45 � 0.03 0.25 0.0 0.0
4 Butanol � 0.05 � 0.14 0.09 0.88 0.0 0.0
5 Pentanol 0.27 0.18 0.09 1.56 0.0 0.0
6 Hexanol 0.54 0.41 0.13 2.03 0.0 0.0
7 Heptanol 0.68 0.74 � 0.06 2.72 0.0 0.0
8 2-Me–Propanol � 0.39 � 0.53 0.14 0.76 0.0 1.0
9 2-Me–Butanol-1 � 0.15 � 0.31 0.16 1.22 0.0 1.0
10 3-Me–Butanol-1 � 0.19 � 0.21 0.02 1.42 0.0 1.0
11 Neopentyl � 0.67 � 0.59 � 0.08 1.31 0.0 2.0
12 Benzyl 0.32 � 0.04 0.36 1.10 0.0 0.0
13 2-Propanol � 0.47 � 0.54 0.07 0.05 0.0 0.0
14 2-Butanol � 0.35 � 0.27 � 0.08 0.61 0.0 0.0
15 2-Pentanol � 0.07 0.01 � 0.08 1.19 0.0 0.0
16 2-Hexanol 0.15 0.28 � 0.13 1.76 0.0 0.0
17 2-Heptanol 0.25 0.54 � 0.29 2.31 0.0 0.0
18 3-Pentanol � 0.37 � 0.65 0.28 1.21 1.0 0.0
19 3-Hexanol � 0.47 � 0.44 � 0.03 1.65 1.0 0.0
20 2-Me–3-Pentanol � 0.89 � 0.82 � 0.07 1.53 1.0 1.0
21 2,4-di–Me–3-Pentanol � 1.38 � 1.29 � 0.09 1.93 2.0 1.0
22* T–Amyl � 2.56 � 0.14 � 2.42 0.89 0.0 0.0
*Outliers.
Table 39. Inactivation of P450 by X-cyclopropanes.
logE 1/2 PRED DEV E1/2
1 1-Me 1-NHCH2C6H5 � 0.18 0.09 � 0.27 1.50
2 1-NHCH2C6H5 0.01 � 0.10 0.11 1.65
3 1 1-di–OH � 0.25 � 0.30 0.05 1.80
4 1-OH 1-OEt 0.0 � 0.36 0.36 1.85
5 1-Me 1-OH � 0.25 � 0.56 0.31 2.0
6 1-OCH2C6H5 � 1.48 � 0.95 � 0.53 2.30
7 1-Me 1-OCH2C6H5 � 1.08 � 0.95 � 0.13 2.30
8 1-Me 1-I � 0.85 � 1.08 0.23 2.40
9 1-I � 1.85 � 1.48 � 0.37 2.70
10 1-Me 1-NHCOC6H5 � 1.20 � 1.21 0.01 2.50
11* 1-Me 1-Br � 0.05 � 1.41 1.36 2.65
12* 1-Br 0.06 � 1.48 1.54 2.70
13* 1-SC6H5 � 2.0 � 0.10 � 1.90 1.65
14 1-Cl � 2.20 � 2.13 � 0.07 3.20
15 1-Me 1-Cl � 2.10 � 2.39 0.29 3.40
*Outliers.
QSAR of Cytochrome P450 125
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changing shape at the inversion point. We now have found many such
examples (Garg et al., 2003).
52. Inhibition of recombinant human P450 2C19 by benzenesulfonamides
(Table 55). Data from Ha-Duong et al. (2001).
log 1=C ¼ 6:03ð�1:7ÞB1 � X þ 0:14ð�0:12ÞL � Y
� 4:94ð�2:6Þ ð55Þ
n = 10, r2 = 0.910, s = 0.175, q2 = 0.836
outliers: X = Me, Y = H; X = CH2CH = CH2, Y = H; X = NH2,
Y = CH2C6H5; X = NH2, Y = H
53. Inhibition of recombinant human P450 2C18 expressed in yeast microsome by
4-X–N–Y–N(2–phenyl–2–H-pyrazole–3-yl) benzene sulfonamides (Table
56). Data from Ha-Duong et al. (2001).
log 1=C ¼ 0:34ð�0:30ÞEs � X � 1:74ð�0:41ÞB1 � Y
þ 2:61ð�0:74Þ ð56Þ
n = 13, r2 = 0.928, s = 0.159, q2 = 0.869
outlier: X = CH2CH = CH2, Y = CH2C6H5
Table 40. Inhibition of P450 1B1 by trans-stilbine analogs.
log1/C PRED DEV L–2
1 2,4-di–OMe–C6H3 8.22 8.28 � 0.06 3.98
2 3,4,5-tri–OMe–C6H2 5.49 5.76 � 0.27 2.06
3* 3,5-di–OMe–C6H3 4.75 5.76 � 1.01 2.06
4 3,4-di–OMe–C6H3 5.52 5.76 � 0.24 2.06
5 4-OMe–C6H4 6.10 5.76 0.34 2.06
6 2-OH–4-OMe–C6H3 6.41 6.66 � 0.25 2.74
7 2-F–4-OMe–C6H3 7.01 6.54 0.48 2.65
*Outlier.
Table 41. Inhibition of glutathione oxidation by 3,5-diX-4-OH acetanilides.
logK PRED DEV MgVol
1* 3,5-di–Me 0.27 � 0.62 0.88 1.45
2 3,5-di–C2H5 0.05 0.06 � 0.01 1.74
3 3,5-di–F � 1.22 � 1.21 � 0.01 1.21
4 3,5-di–Cl � 0.82 � 0.70 � 0.12 1.42
5 3,5-D–Br � 0.23 � 0.45 0.22 1.52
6 3,5-di–I � 0.13 � 0.05 � 0.08 1.69
*Outlier.
126 Hansch et al.
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54. Inhibition of rat hepatic microsomal P450 PB-B by phenothiazine derivatives
(Table 57). Data from Murray (1989).
log 1=C ¼ 0:73ð�0:14ÞC log P þ 1:98ð0:64Þ ð57Þ
n = 9, r2 = 0.957, s = 0.134, q2 = 0.935 outliers: X = H, Y = (CH2)3N(Me)2;
X = H, Y = CH2CH(Me)N(C2H5)2; X = Cl, Y = (CH2)3
–CH2CH2OCOCH3
The authors came to the same conclusion as we have: hydrophobicity is
all important.
55. Inhibition of housefly P450 6D1 by II (Table 58). Data from Scott et al. (2000).
log 1=C ¼ �0:51ð�0:08ÞCMR þ 8:16ð�0:51Þð58Þ
n = 5, r2 = 0.992, s = 0.065, q2 = 0.977
Table 42. Inhibition of P450 BM-3 by ROH.
log1/C PRED DEV MlogP
1 Me 0.15 0.11 0.04 � 0.77
2 C2H5 0.35 0.43 � 0.08 � 0.31
3 C3H7 0.78 0.75 0.03 0.25
4 C4H9 1.05 1.02 0.03 0.88
5 C5H11 1.20 1.21 � 0.01 1.56
6 C6H13 1.26 1.27 � 0.01 2.03
Table 43. Inhibition of testicular P450 by X–adamantane.
log1/C PRED DEV ClogP I–2
1 OCH2 –4-Pyridyl 7.74 7.69 0.06 3.12 1.0
2* OCH(Me)(R)–4-Pyridyl 7.13 8.18 � 1.05 3.43 1.0
3 OCH(Me)(S)–4-Pyridyl 8.74 8.18 0.56 3.43 1.0
4 OC(Me)(Me)–4-Pyridyl 8.57 8.82 � 0.25 3.83 1.0
5 OCH2 –3-Pyridyl 6.34 6.22 0.12 3.12 0.0
6 OCH(Me)(R)–3-Pyridyl 6.82 6.71 0.12 3.43 0.0
7 OCH(Me)(S)–3-Pyridyl 6.64 6.71 � 0.07 3.43 0.0
8 OC(Me)(Me)–3-Pyridyl 7.04 7.34 � 0.31 3.83 0.0
9 NHCH2 –4-Pyridyl 5.80 6.08 � 0.28 2.11 1.0
10 NHCH2 –3-Pyridyl 4.74 4.60 0.14 2.11 0.0
11 NHCH(Me)(R,S)–4-Pyridyl 6.37 6.57 � 0.20 2.42 1.0
12 NHCH(Me)(S)–4-Pyridyl 6.68 6.57 0.11 2.42 1.0
*Outlier.
QSAR of Cytochrome P450 127
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outliers: X = C3H7, Y = (CH2OCH2)3CH2CH2CH3, Z = H; X = Y = Z = H;
X = C3H7, Y = H, Z = OMe
56. Inhibition of cytochrome P450 2C19 by miscellaneous drugs (Table 59). Data
from Lewis et al. (2001).
pKa ¼ �0:59ð�0:19ÞCMR þ 1:24ð�0:36Þbilin CMR þ 7:69ð�1:2Þ ð59Þ
n = 8, r2 = 0.958, s = 0.150, q2 = 0.858 outliers: OMe-pyrazole; fluconazole
Inversion point = 7.18
Another example of an allosteric interaction where activity first decreases
with an increase in CMR and then increases with CMR. See Ref. (Nambo,
1998) for general discussion.
57. Inhibition of dealkylation of pentoxyresorufin from rat liver P450 by
isothiocyanates (Table 60). Data from Conway et al. (1996).
log 1=C ¼ 1:21ð�0:28ÞC log P � 1:95ð�0:67Þbilin C log P
þ 1:63ð�1:1Þ ð60Þ
Table 44. Inhibition of P450 by ROH.
log1/Ki PRED DEV ClogP
1 C2H5 0.80 1.03 � 0.23 � 0.24
2 C3H7 1.53 1.53 0.01 0.29
3 C4H9 2.17 2.02 0.15 0.82
4 C5H11 2.41 2.52 � 0.11 1.35
5 C6H13 3.89 3.02 0.86 1.88
6 C7H15 3.64 3.52 0.12 2.41
7 C8H17 4.07 4.0 0.07 2.94
8 C9H19 4.52 4.46 0.06 3.47
9 C10H21 4.75 4.83 � 0.08 4.0
10 C11H23 4.89 4.94 � 0.06 4.53
11 C12H25 4.46 4.56 � 0.11 5.06
12* C13H27 2.58 � 15.10 17.67 5.58
13 C14H29 2.26 2.28 � 0.02 6.11
14 CHMeC2H5 1.96 1.82 0.15 0.60
15 CHMeC3H7 2.42 2.32 0.10 1.13
16 CHMeC4H9 2.82 2.81 0.01 1.66
17 CHMeC5H11 3.41 3.31 0.10 2.19
18 CHMeC6H13 3.96 3.80 0.16 2.72
19 CY–C6H11 2.39 2.44 � 0.05 1.27
20 CY–C7H13 2.72 2.97 � 0.25 1.83
21 CY–C8H15 3.12 3.49 � 0.37 2.39
22 CH2CY–C3H5 1.60 1.45 0.15 0.21
23 CH2CY–C4H7 2.26 2.50 � 0.24 1.33
24 CH2CY–C5H9 2.57 3.03 � 0.45 1.89
25 CH2CY–C6H11 2.92 3.03 � 0.10 1.89
26 CH2CY–C7H13 3.55 3.55 0.0 2.45
27 CH2CY–C12H23 4.43 4.28 0.15 5.24
*Outlier.
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n = 12, r2 = 0.933, s = 0.321, q2 = 0.903 outlier: (CH2)4SOMe optimum Clog
P = 5.60
58. Inhibition of O–dealkylation of 7-OMe–4-(NHMe)–coumarin by rat
cytochrome P450 2D1 (Table 61). Data from Venhorst et al. (2003).
log 1=C ¼ �0:38ð�0:19ÞC log P þ 0:45ð�0:15ÞCMR
þ 1:13ð�0:90Þ ð61Þ
n = 7, r2 = 0.948, s = 0.142, q2 = 0.807 outliers: codeine, L-propanalol
59. Inhibition of rat cytochrome P450 2D2 dealkylation of 7-OMe–4-(NHMe)–
coumarin by miscellaneous drugs (Table 62). Data from Venhorst et al.
(2003).
log 1=C ¼ 0:51ð�0:35ÞCMR þ 1:23ð�0:92ÞI � OH
þ 1:09ð�2:04Þ ð62Þ
n = 9, r2 = 0.896, s = 0.440, q2 = 0.830 outliers: codeine, quinidine
Table 45. Inhibition of P450 by 1-(X-C6H4)(3,4-imidazolyl–CH2)C6H4.
X Y log1/C PRED DEV I B1–3X B1–4X B5–4X
1 H 4-Imidazolyl–CH2 5.70 5.74 � 0.04 1.0 1.0 1.0 1.0
2 4’-OMe 4-Imidazolyl–CH2 5.10 5.09 0.01 1.0 1.0 1.35 3.07
3 4’-OH 4-Imidazolyl–CH2 5.59 5.59 0.0 1.0 1.0 1.35 1.93
4 4’-F 4-Imidazolyl–CH2 6.01 5.84 0.17 1.0 1.0 1.35 1.35
5 4’-Cl 4-Imidazolyl–CH2 5.85 5.97 � 0.12 1.0 1.0 1.80 1.80
6 4’-Me 4-Imidazolyl–CH2 5.89 5.66 0.22 1.0 1.0 1.52 2.04
7 4’-CN 4-Imidazolyl–CH2 5.92 5.91 0.01 1.0 1.0 1.60 1.60
8 4’-SMe 4-Imidazolyl–CH2 5.07 5.27 � 0.19 1.0 1.0 1.70 3.26
9 3’-OMe 4-Imidazolyl–CH2 5.19 5.41 � 0.22 1.0 1.35 1.0 1.0
10* 3’-OH 4-Imidazolyl–CH2 6.20 5.41 0.79 1.0 1.35 1.0 1.0
11 3’-F 4-Imidazolyl–CH2 5.31 5.41 � 0.10 1.0 1.35 1.0 1.0
12 3’-Cl 4-Imidazolyl–CH2 4.96 4.98 � 0.03 1.0 1.80 1.0 1.0
13 3’-Me 4-Imidazolyl–CH2 5.12 5.25 � 0.13 1.0 1.52 1.0 1.0
14 3’-NO2 4-Imidazolyl–CH2 5.34 5.08 0.26 1.0 1.70 1.0 1.0
15 3’-NHCOMe 4-Imidazolyl–CH2 5.52 5.41 0.11 1.0 1.35 1.0 1.0
16 3’-NH2 4-Imidazolyl–CH2 5.22 5.41 � 0.19 1.0 1.35 1.0 1.0
18 3’,4’-di-OH 4-Imidazolyl–CH2 5.51 5.26 0.25 1.0 1.35 1.35 1.93
19 H 3-Imidazolyl–CH2 5.28 5.12 0.16 0.0 1.0 1.0 1.0
20 4’-OMe 3-Imidazolyl–CH2 4.49 4.47 0.02 0.0 1.0 1.35 3.07
21* 4’-OH 3-Imidazolyl–CH2 5.54 4.97 0.57 0.0 1.0 1.35 1.93
22 4’-F 3-Imidazolyl–CH2 5.21 5.22 � 0.01 0.0 1.0 1.35 1.35
23 4’-Cl 3-Imidazolyl–CH2 5.30 5.35 � 0.05 0.0 1.0 1.80 1.80
24 3’-OMe 3-Imidazolyl–CH2 4.80 4.79 0.01 0.0 1.35 1.0 1.0
25* 3’-OH 3-Imidazolyl–CH2 5.29 4.79 0.50 0.0 1.35 1.0 1.0
26 3’-NHCOMe 3-Imidazolyl–CH2 4.89 4.79 0.10 0.0 1.35 1.0 1.0
27 3’-NH2 3-Imidazolyl–CH2 4.57 4.79 � 0.22 0.0 1.35 1.0 1.0
*Outliers.
QSAR of Cytochrome P450 129
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Table 46. Inhibition of P450 17 by 1-(X–C6H4)(3,4-imidazolyl–CH2)C6H4.
X Y log1/C PRED DEV ClogP I s+ B5-4X
1 H 4-Imidazolyl–CH2 6.01 6.21 � 0.20 3.64 1.0 0.0 1.0
2 4’-OMe 4-Imidazolyl–CH2 5.43 5.63 � 0.19 3.56 1.0 � 0.78 3.07
3 4’-OH 4-Imidazolyl–CH2 6.51 6.62 � 0.11 2.98 1.0 � 0.92 1.93
4 4’-F 4-Imidazolyl–CH2 6.02 6.0 0.02 3.79 1.0 � 0.07 1.35
5 4’-Cl 4-Imidazolyl–CH2 5.24 5.36 � 0.13 4.36 1.0 0.11 1.80
6 4’-Me 4-Imidazolyl–CH2 5.38 5.61 � 0.23 4.14 1.0 � 0.31 2.04
7 4’-CN 4-Imidazolyl–CH2 5.60 5.70 � 0.10 3.08 1.0 0.66 1.60
8 4’-SMe 4-Imidazolyl–CH2 5.11 5.10 0.01 4.20 1.0 � 0.60 3.26
9 3’-OMe 4-Imidazolyl–CH2 6.23 6.17 0.06 3.56 1.0 0.12 1.0
10 3’-OH 4-Imidazolyl–CH2 6.89 6.44 0.45 2.98 1.0 0.12 1.0
11 3’-F 4-Imidazolyl–CH2 6.18 5.91 0.27 3.79 1.0 0.34 1.0
12 3’-Cl 4-Imidazolyl–CH2 5.89 5.63 0.26 4.36 1.0 0.37 1.0
13 3’-Me 4-Imidazolyl–CH2 5.89 6.02 � 0.14 4.14 1.0 � 0.07 1.0
14 3’-NO2 4-Imidazolyl–CH2 5.74 5.85 � 0.11 3.39 1.0 0.71 1.0
15 3’-NHCOMe 4-Imidazolyl–CH2 6.64 6.53 0.11 2.66 1.0 0.21 1.0
16 3’-NH2 4-Imidazolyl–CH2 6.68 6.89 � 0.21 2.42 1.0 � 0.16 1.0
18 3’,4’-di–OH 4-Imidazolyl–CH2 7.06 6.82 0.24 2.38 1.0 � 0.80 1.93
19 H 3-Imidazolyl–CH2 5.66 5.66 0.0 3.64 0.0 0.0 1.0
20 4’-OMe 3-Imidazolyl–CH2 5.35 5.07 0.27 3.56 0.0 � 0.78 3.07
21 4’-OH 3-Imidazolyl–CH2 6.07 6.07 0.0 2.98 0.0 � 0.92 1.93
22 4’-F 3-Imidazolyl–CH2 5.54 5.44 0.09 3.79 0.0 � 0.07 1.35
23 4’-Cl 3-Imidazolyl–CH2 4.89 4.81 0.08 4.36 0.0 0.11 1.80
24 3’-OMe 3-Imidazolyl–CH2 5.43 5.61 � 0.18 3.56 0.0 0.12 1.0
25 3’-OH 3-Imidazolyl–CH2 5.92 5.89 0.03 2.98 0.0 0.12 1.0
26 3’-NHCOMe 3-Imidazolyl–CH2 5.68 5.97 � 0.29 2.66 0.0 0.21 1.0
27* 3’-NH2 3-Imidazolyl–CH2 5.38 6.33 � 0.96 2.42 0.0 � 0.16 1.0
*Outlier.
Table 47. Inhibition of P450 AROM by compounds such as those shown in tables 45 and 46.
log1/C PRED DEV ClogP
1 H 6.22 6.34 � 0.12 3.64
2 4’-OMe 6.25 6.30 � 0.05 3.56
3* 4’-OH 6.24 5.96 0.29 2.98
4 4’-F 6.43 6.43 0.01 3.79
5 4’-Cl 6.70 6.76 � 0.06 4.36
6 3’-OMe 6.60 6.30 0.31 3.56
7* 3’-OH 6.31 5.96 0.35 2.98
8 3’-NHCOMe 5.60 5.78 � 0.17 2.66
9 3’-NH2 5.72 5.63 0.09 2.42
*Outliers.
130 Hansch et al.
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ORDER REPRINTS
I � OH = 1 for presence of OH group.
60. Inhibition of rat cytochrome P450 2D3 dealkylation of 7-OMe–4-(NHMe)–
coumarin by miscellaneous drugs (Table 63). Data from Venhorst et al.
(2003).
log 1=C ¼ 0:65ð�0:19ÞC log P þ 2:16ð�0:50Þ ð63Þ
n = 9, r2 = 0.902, s = 0.315, q2 = 0.849 outliers: sparteine, quinine
61. Inhibition of rat cytochrome P450 2D4 dealkylation of 7-OMe–4-(NHMe)–
coumarin (Table 64). Data from Venhorst et al. (2003)
log 1=C ¼ �3:80ð�0:42ÞCMR þ 1:67ð�0:65Þbilin CMR
þ 5:19ð�2:6Þ ð64Þ
n = 9, r2 = 0.976, s = 0.190, q2 = 0.954 outliers: codeine; quinidine
optimum CMR = 6.44
QSAR 64 is another case of an allosteric reaction.
62. Inhibition of rat cytochrome P450 2D6 dealkylation of 7-OMe–4-(NHMe)–
coumarin (Table 65). Data from Venhorst et al. (2003).
Table 48. Inhibition of 17-a–hydroxylase–C 17,20-lyase P450-17.
log1/C PRED DEV CMR
1 H* 5.92 6.09 � 0.17 7.86
2 F* 6.27 6.07 0.19 7.87
3 OCH3* 5.60 5.34 0.26 8.47
4 H ** 5.68 5.75 � 0.07 8.14
5 F ** 5.77 5.73 0.04 8.16
6 OCH3 ** 5.0 5.0 0.0 8.76
*Outlier: OCH3.
Parent structures: .
Table 49. Inhibition of 17-a–hydroxylase–C 17,20-lyase P450–17.
log1/C PRED DEV MgVol
1 H* 6.77 6.74 0.03 2.03
2 F* 6.62 6.66 � 0.04 2.05
3 OCH3* 5.74 5.79 � 0.05 2.23
4 H* 6.60 6.59 0.01 2.07
5 F* 5.95 6.50 � 0.55 2.08
6 OCH3* 5.68 5.64 0.04 2.27
*Outlier: F.
QSAR of Cytochrome P450 131
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ORDER REPRINTS
log 1=C ¼ �20:37ð�11:1ÞMgVol þ 5:95ð�2:79ÞMgVol2
þ 21:65ð�10:8Þ ð65Þ
n = 9, r2 = 0.936, s = 0.393, q2 = 0.882 outliers: codeine, quinine
Another example of an allosteric reaction.
63. Inhibition of P450 from rat liver microsomes dealkylation of ethoxyresrufin
treated rats by isothiocyanates (Table 66). Data from Conway et al. (1996)
log 1=C ¼ 0:68ð�0:23ÞCMR þ 0:93ð�1:3Þ ð66Þ
n = 8, r2 = 0.902, s = 0.320, q2 = 0.804 outlier: (CH2)6C6H5
64. Binding of b-blockers to cytochrome P450 I1D6 (Table 67). Data from
Ferrari et al. (1991).
Table 50. Inhibition of rat testicular P450 17 by X–C6H4 –C6H4CH2 –Imidazolyl.
X Y log1/C PRED DEV I�Y B1�3X B1�4X B5�4X
1 H 4-CH2 –Imidazolyl 5.70 5.74 � 0.04 1.0 1.0 1.0 1.0
2 4-OMe 4-CH2 –Imidazolyl 5.10 5.09 0.01 1.0 1.0 1.35 3.07
3 4-OH 4-CH2 –Imidazolyl 5.59 5.59 0.0 1.0 1.0 1.35 1.93
4 4-F 4-CH2 –Imidazolyl 6.01 5.84 0.17 1.0 1.0 1.35 1.35
5 4-Cl 4-CH2 –Imidazolyl 5.85 5.97 � 0.12 1.0 1.0 1.80 1.80
6 4-Me 4-CH2 –Imidazolyl 5.89 5.66 0.22 1.0 1.0 1.52 2.04
7 4-CN 4-CH2 –Imidazolyl 5.92 5.91 0.01 1.0 1.0 1.60 1.60
8 4-SMe 4-CH2 –Imidazolyl 5.07 5.27 � 0.19 1.0 1.0 1.70 3.26
9 3-OMe 4-CH2 –Imidazolyl 5.19 5.41 � 0.22 1.0 1.35 1.0 1.0
10* 3-OH 4-CH2 –Imidazolyl 6.20 5.41 0.79 1.0 1.35 1.0 1.0
11 3-F 4-CH2 –Imidazolyl 5.31 5.41 � 0.10 1.0 1.35 1.0 1.0
12 3-Cl 4-CH2 –Imidazolyl 4.96 4.98 � 0.03 1.0 1.80 1.0 1.0
13 3-Me 4-CH2 –Imidazolyl 5.12 5.25 � 0.13 1.0 1.52 1.0 1.0
14 3-NO2 4-CH2 –Imidazolyl 5.34 5.08 0.26 1.0 1.70 1.0 1.0
15 3-NHCOMe 4-CH2 –Imidazolyl 5.52 5.41 0.11 1.0 1.35 1.0 1.0
16 3-NH2 4-CH2 –Imidazolyl 5.22 5.41 � 0.19 1.0 1.35 1.0 1.0
18 3,4-di–OH 4-CH2 –Imidazolyl 5.51 5.26 0.25 1.0 1.35 1.35 1.93
19 H 3-CH2 –Imidazolyl 5.28 5.12 0.16 0.0 1.0 1.0 1.0
20 4-OMe 3-CH2 –Imidazolyl 4.49 4.47 0.02 0.0 1.0 1.35 3.07
21* 4-OH 3-CH2 –Imidazolyl 5.54 4.97 0.57 0.0 1.0 1.35 1.93
22 4-F 3-CH2 –Imidazolyl 5.21 5.22 � 0.01 0.0 1.0 1.35 1.35
23 4-Cl 3-CH2 –Imidazolyl 5.30 5.35 � 0.05 0.0 1.0 1.80 1.80
24 3-OMe 3-CH2 –Imidazolyl 4.80 4.79 0.01 0.0 1.35 1.0 1.0
25* 3-OH 3-CH2 –Imidazolyl 5.29 4.79 0.50 0.0 1.35 1.0 1.0
26 3-NHCOMe 3-CH2 –Imidazolyl 4.89 4.79 0.10 0.0 1.35 1.0 1.0
27 3-NH2 3-CH2 –Imidazolyl 4.57 4.79 � 0.22 0.0 1.35 1.0 1.0
*Outliers.
132 Hansch et al.
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ORDER REPRINTS
log 1=Ki ¼ 0:41ð�0:20Þ log P þ 4:55ð�0:25Þ ð67Þ
n = 6, r2 = 0.890, s = 0.205, q2 = 0.772 outliers: LT-18502; acebutolol
65. Inhibition of cytochrome P450 UT-F by phenothiazines (Table 68). Data
from Murray (1989).
log 1=C ¼ �0:13ð�0:09ÞB5 � X þ 4:42ð�0:22Þ ð68Þ
n = 5, r2 = 0.871, s = 0.034, q2 = 0.765
outlier: X = Cl, Y = (CH2)3 CH2CH2OH
66. Inhibition of cytochrome P450 UT-A by phenothiazines (Table 69). Data
from Murray (1989).
log 1=C ¼ 0:15ð�0:08ÞB5 � X þ 4:62ð�0:20Þ ð69Þ
Table 51. Inhibition of human placental P450 by X–C6H4 –C6H4CH2 –imidazolyl.
X Y log1/C PRED DEV ClogP I�Y s+ B5�4X
1 H 4-CH2 –Imidazolyl 6.01 6.21 � 0.20 3.64 1.0 0.0 1.0
2 4-OMe 4-CH2 –Imidazolyl 5.43 5.63 � 0.19 3.56 1.0 � 0.78 3.07
3 4-OH 4-CH2 –Imidazolyl 6.51 6.62 � 0.11 2.98 1.0 � 0.92 1.93
4 4-F 4-CH2 –Imidazolyl 6.02 6.0 0.02 3.79 1.0 � 0.07 1.35
5 4-Cl 4-CH2 –Imidazolyl 5.24 5.36 � 0.13 4.36 1.0 0.11 1.80
6 4-Me 4-CH2 –Imidazolyl 5.38 5.61 � 0.23 4.14 1.0 � 0.31 2.04
7 4-CN 4-CH2 –Imidazolyl 5.60 5.70 � 0.10 3.08 1.0 0.66 1.60
8 4-SMe 4-CH2 –Imidazolyl 5.11 5.10 0.01 4.20 1.0 � 0.60 3.26
9 3-OMe 4-CH2 –Imidazolyl 6.23 6.17 0.06 3.56 1.0 0.12 1.0
10 3-OH 4-CH2 –Imidazolyl 6.89 6.44 0.45 2.98 1.0 0.12 1.0
11 3-F 4-CH2 –Imidazolyl 6.18 5.91 0.27 3.79 1.0 0.34 1.0
12 3-Cl 4-CH2 –Imidazolyl 5.89 5.63 0.26 4.36 1.0 0.37 1.0
13 3-Me 4-CH2 –Imidazolyl 5.89 6.02 � 0.14 4.14 1.0 � 0.07 1.0
14 3-NO2 4-CH2 –Imidazolyl 5.74 5.85 � 0.11 3.39 1.0 0.71 1.0
15 3-NHCOMe 4-CH2 –Imidazolyl 6.64 6.53 0.11 2.66 1.0 0.21 1.0
16 3-NH2 4-CH2 –Imidazolyl 6.68 6.89 � 0.21 2.42 1.0 � 0.16 1.0
18 3,4-di–OH 4-CH2 –Imidazolyl 7.06 6.82 0.24 2.38 1.0 � 0.80 1.93
19 H 3-CH2 –Imidazolyl 5.66 5.66 0.0 3.64 0.0 0.0 1.0
20 4-OMe 3-CH2 –Imidazolyl 5.35 5.07 0.27 3.56 0.0 � 0.78 3.07
21 4-OH 3-CH2 –Imidazolyl 6.07 6.07 0.0 2.98 0.0 � 0.92 1.93
22 4-F 3-CH2 –Imidazolyl 5.54 5.44 0.09 3.79 0.0 � 0.07 1.35
23 4-Cl 3-CH2 –Imidazolyl 4.89 4.81 0.08 4.36 0.0 0.11 1.80
24 3-OMe 3-CH2 –Imidazolyl 5.43 5.61 � 0.18 3.56 0.0 0.12 1.0
25 3-OH 3-CH2 –Imidazolyl 5.92 5.89 0.03 2.98 0.0 0.12 1.0
26 3-NHCOMe 3-CH2 –Imidazolyl 5.68 5.97 � 0.29 2.66 0.0 0.21 1.0
27* 3-NH2 3-CH2 –Imidazolyl 5.38 6.33 � 0.96 2.42 0.0 � 0.16 1.0
*Outlier.
QSAR of Cytochrome P450 133
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ORDER REPRINTS
n = 5, r2 = 0.922, s = 0.047, q2 = 0.679 outliers: X = H, Y = CH2CH(Me)
N(C2H5)2; X = 5-Me, Y = (CH2)2
67. Inhibition of binding affinity of dextramethorphan by 4-substituted 7-
methoxy coumarin analogs of binding to P450 2D6 expressed in human
lymphoblasts (Table 70). Data from Venhorst et al. (2000).
log 1=C ¼ 0:66ð�0:25ÞL � X � 0:88ð�1:5Þ ð70Þ
n = 6, r2 = 0.931, s = 0.308, q2 = 0.852 outlier: CH2–pyridinium
68. Conversion of cytochrome P450 from rabbit liver microsomes to P470 by
phenols (Table 71). Data from Ichikawa and Yamano (1967).
Table 52. Inhibition of P450 2A5 by miscellaneous chemicals.
log1/C PRED DEV MgVol
1 g-Butyrolactone 1.73 1.35 0.38 0.64
2 5,6-Dihydro–2H-Pyran–2-one 2.22 2.11 0.11 0.74
3 2H–Pyran–2-one 2.28 1.78 0.50 0.69
4 Caprolactone 3.05 3.39 � 0.34 0.92
5 g–Valerolactone 2.23 2.43 � 0.20 0.78
6 g–Heptalactone 4.54 4.22 0.32 1.06
7 g–Octanoic–Lactone 5.24 4.87 0.37 1.20
8 g–Decano–Lactone 5.68 5.51 0.17 1.48
9 g–Undecano–Lactone 5.41 5.45 � 0.04 1.62
10 g–Dodecano–Lactone 5.41 5.11 0.30 1.77
11 D–Hexalactone 2.66 3.39 � 0.73 0.92
12 Undecanoic-D–Lactone 4.93 5.45 � 0.52 1.62
13 2-Coumarone 4.33 3.67 0.66 0.96
14 2-Indanone 4.29 4.14 0.15 1.05
15 Indan 4.08 4.06 0.02 1.03
16 2-Benzoxazolinone 2.98 3.41 � 0.43 0.92
17 7-Methyl–Coumarin 5.40 4.87 0.53 1.20
18 Butylcyclohexane 5.24 5.43 � 0.19 1.41
19 Butylbenzene 4.79 5.14 � 0.35 1.28
20 Biphenyl 4.54 5.26 � 0.72 1.32
21 g–Phenyl-g–Butyrolactone 5.62 5.03 0.59 1.25
22 4-Methoxy–2(5H)–Furanone 2.14 2.54 � 0.40 0.79
23 4,5-Dimethyl–Alfa–Pyrone 3.38 3.73 � 0.35 0.97
24 D–Valerolactone 2.01 2.43 � 0.42 0.78
25 D–Decano–Lactone 5.42 5.51 � 0.09 1.48
26 2,3-Dihydro–Benzofuran 4.10 3.57 0.53 0.95
27 g–Nonanoiclactone 5.72 5.31 0.41 1.34
28 g–Caprolactone 3.14 3.39 � 0.25 0.92
134 Hansch et al.
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ORDER REPRINTS
Table 53. Inhibition of P450 2C8 by .
X Y log1/C PRED DEV s,X L�X L�Y
1 Me H 3.66 3.62 0.04 � 0.17 2.87 2.06
2 CH2CH CH2 H 5.0 4.70 0.30 � 0.14 5.11 2.06
3 NH2 Me 4.30 4.24 0.06 � 0.66 2.78 2.87
4 NH2 C2H5 4.89 4.70 0.18 � 0.66 2.78 4.11
5 NH2 C3H7 5.10 5.01 0.09 � 0.66 2.78 4.92
6 NH2 CHMe2 4.52 4.70 � 0.18 � 0.66 2.78 4.11
7 NH2 C4H9 5.40 5.48 � 0.08 � 0.66 2.78 6.17
8 NH2 (CH2)2CHMe2 5.52 5.48 0.05 � 0.66 2.78 6.17
9 NH2 CH2C6H5 4.82 4.90 � 0.07 � 0.66 2.78 4.62
10 CH2CH CH2 Me 4.70 5.0 � 0.30 � 0.14 5.11 2.87
11* CH2CH CH2 CH2C6H5 4.52 5.66 � 1.13 � 0.14 5.11 4.62
12 Me Me 3.74 3.92 � 0.18 � 0.17 2.87 2.87
13 Me C3H7 4.82 4.69 0.14 � 0.17 2.87 4.92
14 NH2 H 3.89 3.94 � 0.05 � 0.66 2.78 2.06
*Outlier.
Table 54. Inhibition of P450 2C9 by .
X Y log1/C PRED DEV L�Y
1 Me H 6.22 5.96 0.26 2.06
2 3-NO2 –C6H4 H 5.40 5.96 � 0.57 2.06
3 CH2CH CH2 H 6.0 5.96 0.04 2.06
4* 3–NH2 –C6H4 H 4.92 9.37 � 4.45 2.06
5* NH2 Me 4.0 9.41 � 5.41 2.87
6 NH2 C2H5 4.05 4.33 � 0.28 4.11
7 NH2 C3H7 4.26 4.31 � 0.05 4.92
8 NH2 CHMe2 4.10 4.33 � 0.23 4.11
9 NH2 C4H9 4.30 4.37 � 0.07 6.17
10 NH2 (CH2)2CHMe2 4.22 4.37 � 0.15 6.17
11 NH2 CH2C6H5 4.26 4.31 � 0.05 4.62
12 3-NO2 –C6H4 (CH2)2OH 4.70 4.31 0.39 4.79
13 Me Me 5.0 4.92 0.08 2.87
14 Me C3H7 4.70 4.31 0.38 4.92
15 NH2 H 6.22 5.96 0.26 2.06
*Outliers.
QSAR of Cytochrome P450 135
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ORDER REPRINTS
Table 55. Inhibition of P450 2C19 by .
X Y log1/C PRED DEV B1�X L�Y
1* Me H 4.0 4.52 � 0.52 1.52 2.06
2* CH2CH CH2 H 3.35 4.52 � 1.17 1.52 2.06
3 NH2 Me 3.70 3.61 0.09 1.35 2.87
4 NH2 C2H5 3.65 3.79 � 0.14 1.35 4.11
5 NH2 C3H7 3.60 3.91 � 0.31 1.35 4.92
6 NH2 CHMe2 3.89 3.79 0.09 1.35 4.11
7 NH2 C4H9 4.22 4.09 0.13 1.35 6.17
8 NH2 (CH2)2CHMe2 4.22 4.09 0.13 1.35 6.17
9* NH2 CH2C6H5 4.35 3.86 0.48 1.35 4.62
10 CH2CH CH2 Me 4.70 4.64 0.06 1.52 2.87
11 CH2CH CH2 CH2C6H5 4.70 4.89 � 0.19 1.52 4.62
12 Me Me 4.70 4.64 0.06 1.52 2.87
13 Me C3H7 5.0 4.93 0.07 1.52 4.92
*Outliers.
Table 56. Inhibition of P450 2C18 by .
X Y log1/C PRED DEV ES�X B1�Y
1 Me H 3.77 3.94 � 0.17 � 1.24 1.0
3 CH2CH CH2 H 3.82 3.87 � 0.05 � 1.43 1.0
5 NH2 Me 4.82 5.05 � 0.23 � 0.61 1.52
6 NH2 C2H5 5.15 5.05 0.10 � 0.61 1.52
7 NH2 C3H7 5.10 5.05 0.04 � 0.61 1.52
8 NH2 CHMe2 5.52 5.72 � 0.19 � 0.61 1.90
9 NH2 C4H9 5.22 5.05 0.17 � 0.61 1.52
10 NH2 (CH2)2CHMe2 5.05 5.05 � 0.01 � 0.61 1.52
11 NH2 CH2C6H5 5.15 5.05 0.10 � 0.61 1.52
20 CH2CH CH2 Me 5.0 4.78 0.22 � 1.43 1.52
21* CH2CH CH2 CH2C6H5 3.90 4.78 � 0.87 � 1.43 1.52
22 Me Me 4.92 4.84 0.08 � 1.24 1.52
23 Me C3H7 4.70 4.84 � 0.14 � 1.24 1.52
24 NH2 H 4.22 4.15 0.07 � 0.61 1.0
*Outlier.
136 Hansch et al.
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ORDER REPRINTS
log 1=C ¼ 0:57ð�0:08Þ log P þ 0:36ð�0:19Þ ð71Þ
n = 13, r2 = 0.959, s = 0.131, q2 = 0.942 outlier: pentachlorophenol
69. Conversion of P450 from rabbit liver microsomes to P420 by X–C6H5NH2
(Table 72). Data from Ichikawa and Yamano (1967).
Table 57. Inhibition of P450 PB-B.
X Y log1/C PRED DEV ClogP
1 H (CH2)3N(CH3)2 5.82 5.26 0.56 4.40
2 Cl (CH2)3N(CH3)2 5.74 5.91 � 0.17 5.30
3 H CH2CH(CH3)N(CH3)2 5.40 5.26 0.14 4.40
4* H CH2CH(CH3)N(C2H5)2 5.12 6.03 � 0.90 5.46
5 CF3 (CH2)3 –CYCLO–N(CH2CH2)2NCH3 5.24 5.47 � 0.24 4.69
6 Cl (CH2)3 –CYCLO–N(CH2CH2)2NCH3 5.07 5.25 � 0.18 4.38
7 CF3 (CH2)3 –CYCLO–N(CH2CH2)2N(CH2)2OH 5.03 5.06 � 0.03 4.12
8 Cl (CH2)3CYCLO–N(CH2CH2)2N–(CH2)2OH 4.82 4.83 � 0.01 3.81
9 SCH3 (CH2)2 –(N-CH3-PIPERIDIN–2-YL) 6.43 6.42 0.01 6.0
10 SC2H5 (CH2)3 –CYCLO–N(CH2CH2)2NCH3 5.43 5.37 0.06 4.55
11* Cl (CH2)3 –CYCLO–N(CH2CH2)2NCH2CH2-
OCOCH3
4.92 6.68 � 1.76 6.36
12 CN (CH2)3 –(4-OH–PIPERIDIN–1-YL) 4.28 4.42 � 0.15 3.24
*Outliers.
Table 58. Inhibition of P450 6D1 by .
X Y Z log1/C PRED DEV CMR
1* CH2CH2CH3 (CH2OCH2)3-
CH2CH2CH3
H 6.37 3.35 3.02 9.31
2 CH2CH2CH3 H OCH3 6.19 5.65 0.54 5.29
3 CH2CH2CH3 H H 5.85 6.0 � 0.15 4.67
4 CH CHCH2CH3 H H 5.47 5.71 � 0.24 5.19
5 n-HEXYL H H 5.14 5.20 � 0.07 6.06
6 C(CH3)2OCH2
C � CCH3
H H 4.80 4.92 � 0.13 6.55
7* H H H 4.77 6.80 � 2.03 3.28
8 H (CH2OCH2)3-
CH2CH2CH3
H 4.18 4.14 0.04 7.91
*Outliers.
QSAR of Cytochrome P450 137
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ORDER REPRINTS
log 1=C ¼ 0:67ð�0:14Þ log P þ 0:34ð�0:19Þ ð72Þ
n = 7, r2 = 0.969, s = 0.079, q2 = 0.935
For quite different compounds, the slopes and intercepts of QSAR 71 and
72 are remarkably similar.
70. Dissociation of the isostrole metabolite – cytochrome P450 complex
(Table 73). Data from Dickings et al. (1979).
log Ks ¼ 0:58ð�0:13ÞC log P þ 2:24ð�0:34Þ ð73Þ
n = 7, r2 = 0.972, s = 0.125, q2 = 0.904
Table 59. Inhibition of P450 2C19 by miscellaneous drugs.
pKa PRED DEV CMR
1 S–Mephenytoin 4.22 4.10 0.12 6.10
2* Omeprazole 5.39 13.71 � 8.33 9.36
3 Propranolol 3.95 3.92 0.03 7.83
4 Diazepam 4.0 4.05 � 0.05 8.12
5 R–Warfarin 4.49 4.39 0.11 8.72
6 Phenytoin 3.55 3.78 � 0.22 7.22
7 Ly307640 5.04 5.08 � 0.05 9.82
8* Fluconazole 5.70 12.39 � 6.69 7.30
9 Tranylcypromine 5.10 5.13 � 0.03 4.31
10 Desmethyldiazepam 3.94 3.85 0.09 7.65
*Outliers.
Table 60. Inhibition of dealkylation of pentoxyresorfin by X–N C S.
log1/C PRED DEV ClogP
1 CH2CH CH2 4.11 3.96 0.14 1.94
2* (CH2)4SOCH3 4.17 1.53 2.64 0.15
3 CH2C6H5 5.30 5.48 � 0.18 3.20
4 CH2CH2C6H5 5.74 5.55 0.19 3.26
5 (CH2)4C6H5 6.77 6.60 0.17 4.17
6 (CH2)6C6H5 7.60 7.46 0.14 5.23
7 (CH2)8C6H5 7.28 7.35 � 0.07 6.29
8 (CH2)10C6H5 6.77 6.75 0.02 7.35
9 CH(C6H5)CH2C6H5 7.35 7.39 � 0.05 5.08
10 CH2CH(C6H5)2 6.89 7.12 � 0.24 4.70
11 (CH2)5CH3 6.12 6.20 � 0.07 3.81
12 CH(CH3)CH2CH2CH2CH3 5.36 5.94 � 0.58 3.59
13 C(CH3)2CH2C(CH3)3 7.22 6.70 0.53 4.26
*Outlier.
138 Hansch et al.
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ORDER REPRINTS
71. Dissociation of X–C6H4–COOH P450 complex (Table 74). Data from Blake
and Coon (1980).
log k2=ki ¼ �0:10ð�0:08Þs � 0:96ð�0:06ÞC log P
þ 1:13ð�0:07Þ ð74Þ
n = 17, r2 = 0.991, s = 0.046, q2 = 0.985
72. Dissociation of X–C6H4CH2COOOH P450 complex (Table 75). Data from
Blake and Coon (1980).
log 1=C ¼ �0:83ð�0:16Þp � 0:53ð�0:24Þs þ 1:17ð�0:11Þ ð75Þ
n = 11, r2 = 0.951, s = 0.088, q2 = 0.897 outlier: 4-Br
73. Dissociation of X–C6H4C(Me)2OOH P450 complex (Table 76). Data from
Blake and Coon (1980).
Table 61. Inhibition of O-dealkylation of 7-OMe, 4-(NHMe)–coumarin by miscellaneous drugs.
log1/C PRED DEV ClogP CMR
1* Codeine 2.88 4.47 � 1.59 0.98 8.18
2 Debrisoquine 3.28 3.21 0.06 0.90 5.30
3 Dextromethorphan 3.58 3.56 0.02 3.95 8.16
4 4-CH2NMe2-7–OMe–Coumarin 3.48 3.56 � 0.08 1.58 6.54
5 Nortriptyline 3.69 3.69 0.01 4.32 8.69
6 D –Propranolol 3.74 3.78 � 0.04 2.75 7.83
1* L –Propranolol 3.24 3.78 � 0.54 2.75 7.83
8 Quinine 4.33 4.50 � 0.17 2.79 9.48
9 Quinidine 4.70 4.50 0.20 2.79 9.48
*Outliers.
Table 62. Inhibition of P450 2D2 dealkylation of 7-OMe-4 – (NHMe) Coumarin by
miscellaneous drugs.
log1/C PRED DEV ClogP
1 Codeine 2.39 2.79 � 0.40 0.98
2 Debrisoquine 2.76 2.74 0.02 0.90
3 Dextromethorphan 4.73 4.71 0.02 3.95
4 4-CH2NMe2 –7-OMe–Coumarin 3.06 3.18 � 0.12 1.58
5 Nortriptyline 4.85 4.95 � 0.11 4.32
6 Phenformine 2.72 2.42 0.30 0.40
7 D –Propranolol 3.81 3.94 � 0.13 2.75
8 L –Propranolol 3.76 3.94 � 0.18 2.75
9* Sparteine 2.67 3.92 � 1.25 2.72
10* Quinine 4.92 3.96 0.96 2.79
11 Quinidine 4.57 3.96 0.61 2.79
*Outliers.
QSAR of Cytochrome P450 139
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ORDER REPRINTS
log k2=ki ¼ �0:56ð�0:42Þs � 1:07ð�0:29ÞC log P
þ 2:24ð�0:44Þ ð76Þ
n = 6, r2 = 0.980, s = 0.056, q2 = 0.893
In QSAR 74–76, as one would expect, the log P term is negative.
74. Binding of aromatic hydrocarbons to rat P450 (Table 77). Data from Backes
et al. (1982).
log Ks ¼ 0:79ð�0:38Þ log P þ 1:46ð�1:25Þ ð77Þ
n = 5, r2 = 0.937, s = 0.205, q2 = 0.864
75. Dissociation of 4-X–C6H4Me from cytochrome P450 2B4 (Table 78). Data
from Lewis et al. (1995).
Table 63. Inhibition of P450 2D3 O-dealkylation of 7-OMe, 4– (NHMe) coumarin by
miscellaneous drugs.
log1/C PRED DEV CMR I�OH
1* Codeine 3.62 6.52 � 2.89 8.18 1.0
2 Debrisoquine 3.97 3.81 0.16 5.30 0.0
3 Dextromethorphan 5.25 5.28 � 0.03 8.16 0.0
4 4-CH2NMe2 –7–OMe–Coumarin 3.51 4.45 � 0.93 6.54 0.0
5 Nortriptyline 5.72 5.55 0.17 8.69 0.0
6 Phenformine 4.34 4.18 0.16 6.03 0.0
7 D –Propranolol 6.38 6.34 0.04 7.83 1.0
8 L–Propranolol 6.46 6.34 0.12 7.83 1.0
9 Sparteine 5.14 4.68 0.46 7.0 0.0
10 Quinine 7.03 7.18 � 0.16 9.48 1.0
11* Quinidine 5.55 7.18 � 1.63 9.48 1.0
*Outliers.
Table 64. Inhibition of P450 2D4 O– dealkylation of 7-OMe, 4-(NHMe) coumarin by
miscellaneous drugs.
log1/C PRED DEV ClogP
1 Codeine 2.39 2.79 � 0.40 0.98
2 Debrisoquine 2.76 2.74 0.02 0.90
3 Dextromethorphan 4.73 4.71 0.02 3.95
4 4-CH2NMe2 –7-OMe–Coumarin 3.06 3.18 � 0.12 1.58
5 Nortriptyline 4.85 4.95 � 0.11 4.32
6 Phenformine 2.72 2.42 0.30 0.40
7 D –Propranolol 3.81 3.94 � 0.13 2.75
8 L–Propranolol 3.76 3.94 � 0.18 2.75
9* Sparteine 2.67 3.92 � 1.25 2.72
10* Quinine 4.92 3.96 0.96 2.79
11 Quinidine 4.57 3.96 0.61 2.79
*Outliers.
140 Hansch et al.
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ORDER REPRINTS
log Kd ¼ �0:77ð�0:54ÞC log P � 0:67ð�1:2Þ ð78Þ
n = 7, r2 = 0.938, s = 0.134, q2 = 0.800 outlier: 4-CN
76. Dissociation of 4-X–C6H4Me from P450 2B4 (Table 79). Data from Lewis
et al. (1995).
log Kd ¼ �1:36ð�0:19ÞC log P þ 2:45ð�1:8ÞER þ 5:94ð�0:65Þ ð79Þ
n = 8, r2 = 0.986, s = 0.113 , q2 = 0.969 outliers: 4-CN, 4-NO2
ER is a radical parameter (Lewis et al., 2001). The usual Hammett
parameters of s, s+ and s� are not of use in QSAR 79. ER has a positive
coefficient suggesting that radical formation promotes dissociation.
77. Binding to b–naphthoflavone induced microsomal P450 rat liver of 3,5-di–
X–4-OH acetanilide (Table 80). Data from Bessems et al. (1996)
Table 65. Inhibition of P450 2D6 O-dealkylation of 7-OMe, 4-(NHMe) coumarin by
miscellaneous drugs.
log1/C PRED DEV CMR
1* Codeine 2.65 15.67 � 13.02 8.18
2 Debrisoquine 3.13 3.18 � 0.05 5.30
3 Dextromethorphan 3.87 4.10 � 0.23 8.16
4 4-CH2NMe2 –7-OMe–Coumarin 2.93 2.91 0.01 6.54
5 Nortriptyline 4.71 4.74 � 0.03 8.69
6 Phenformine 3.08 2.96 0.12 6.03
7 D –Propranolol 3.93 3.73 0.21 7.83
8 L –Propranolol 3.88 3.73 0.15 7.83
9 Sparteine 2.83 3.04 � 0.21 7.0
10 Quinine 5.77 5.74 0.02 9.48
11* Quinidine 4.33 17.34 � 13.01 9.48
*Outliers.
Table 66. Inhibition of P450 O-dealkylation of 7-OMe, 4-(NHMe) by isothiocyanates.
PRED DEV Log 1/C CMR
1 CH2C6H5 4.13 0.13 4.27 4.70
2 CH2CH2C6H5 4.45 � 0.12 4.33 5.16
3 (CH2)4C6H5 5.08 � 0.33 4.76 6.09
4* (CH2)6C6H5 5.72 � 0.56 5.15 7.02
5 CH(C6H5)CH2C6H5 6.17 � 0.12 6.05 7.67
6 CH2CH(C6H5)2 6.17 0.42 6.59 7.67
7 (CH2)5CH3 4.00 0.34 4.35 4.51
8 CH(CH3)CH2CH2CH2CH3 4.00 0.08 4.08 4.51
9 C(CH3)2CH2C(CH3)3 4.64 � 0.40 4.24 5.43
*Outlier.
QSAR of Cytochrome P450 141
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ORDER REPRINTS
log Vmax=Km ¼ �0:53ð�0:22ÞEs � 0:20ð�0:47Þ ð80Þ
n = 7, r2 = 0.889, s = 0.222, q2 = 0.722 outlier: 3,5-di-C3H7
78. Binding of Y–HN–X–CHCH2C6H4 to rabbit P450 (Table 81). Data from
Nambo Nambo (1998).
log Vmax ¼ 0:30ð�0:19ÞC log P � 1:63ð�0:25ÞI þ 1:68ð�0:42Þ ð81Þ
n = 16, r2 = 0.944, s = 0.198, q2 = 0.904 outlier: X = H, Y = H
I = 1 for Y = H
79. Affinity of X–C6H4N(Me)2 to rabbit P450 (Table 82). Data from Nambo
Nambo (1998).
log 1=Km ¼ 0:70ð�0:36ÞC log P � 0:21ð�0:06ÞC log P2
� 0:50ð�0:23ÞB1 þ 4:43ð�0:57Þ ð82Þ
n = 16, r2 = 0.981, s = 0.123, q2 = 0.952 optimum Clog P = 1.64
80. Biomolecular reduction rate of miscellaneous aromatic nitro compounds by
cytochrome P450 reductase (Table 83). Data from Cenas et al. (1994).
Table 67. Binding of b-blockers to P450 106.
log1/Ki PRED DEV logP
1 Bufuralol 5.32 5.30 0.02 1.80
2 Propranolol 5.17 5.10 0.07 1.32
3 Betaxolol 4.87 5.02 � 0.15 1.13
4 Oxprenolol 5.0 4.75 0.25 0.48
5* LT-18502 5.12 4.68 0.44 0.30
6* Acebutolol 4.14 4.54 � 0.40 � 0.04
7 Pindolol 4.24 4.51 � 0.27 � 0.10
8 Atenolol 3.92 3.85 0.07 � 1.70
*Outliers.
Table 68. Inhibition of cytochrome P450 UTF by phenothiazines.
X Y log1/C PRED DEV B5�X
1 CF3 (CH2)3 –CYCLO–N(CH2CH2)2NCH3 4.06 4.09 � 0.03 2.61
2 Cl (CH2)3 –CYCLO–N(CH2CH2)2NCH3 4.19 4.19 0.0 1.80
3 CF3 (CH2)3 –CYCLO–N(CH2CH2)2N(CH2)2OH 4.14 4.09 0.05 2.61
4* Cl (CH2)3CYCLO–N(CH2CH2)2N–(CH2)2OH 4.28 4.19 0.09 1.80
5 SCH3 (CH2)2-(N–CH3 –PIPERIDIN–2–YL) 4.0 4.01 � 0.01 3.26
6 Cl (CH2)3 –CYCLO–N(CH2CH2)2NCH2CH2-
OCOCH3
4.18 4.19 � 0.01 1.80
*Outlier.
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ORDER REPRINTS
log kcat=Km ¼ 11:4ð�2:26ÞE þ 7:86 ð83Þ
n = 6, r2 = 0.980, s = 0.164, r2 = 0.951
E is the single electron reduction potential. Since the correlation is very
high, there appears to be no hydrophobic effect.
81. NADPH–cytochrome P450 reductase action on miscellaneous aromatic nitro
compounds (Table 84). Data from Virginia and Mason (1989).
log Vmax=Km ¼ 15:1ð�6:1ÞE þ 2:31ð�2:26Þ ð84Þ
n = 5, r2 = 0.954, s = 0.379, q2 = 0.878
QSAR 84 is not as sharp as QSAR 83, although the data sets are similar.
82. Binding of aliphatic amines to rat liver cytochrome P450 2B1 (Table 85).
Data from Lewis and Dickens (2001).
pKi ¼ 1:14ð�0:00ÞC log P � 1:82ð�0:001Þ ð85Þ
n = 7, r2 = 1.00, s = 0.00, q2 = 1.00 outlier: C5H12NH2
83. Binding of miscellaneous drugs to cytochrome P450 2C19 (Table 86). Data
from Lewis and Dickens (2001).
Table 69. Inhibition of P450 UT-A by phenothiazaines.
X Y log1/C PRED DEV B5�X
1* H CH2CH(CH3)N(C2H5)2 4.16 4.48 � 0.32 1.0
2 Cl (CH2)3 –CYCLO–N(CH2CH2)2NCH3 4.33 4.36 � 0.03 1.80
3 CF3 (CH2)3 –CYCLO–N(CH2CH2)2N(CH2)2OH 4.28 4.24 0.04 2.61
4 Cl (CH2)3CYCLO–N(CH2CH2)2N–(CH2)2OH 4.41 4.36 0.05 1.80
5* SCH3 (CH2)2 –(N-CH3 –PIPERIDIN–2-YL) 4.37 4.14 0.22 3.26
6 SC2H5 (CH2)3 –CYCLO–N(CH2CH2)2NCH3 4.03 4.04 � 0.01 3.97
7 Cl (CH2)3 –CYCLO–N(CH2CH2)2NCH2CH2-
OCOCH3
4.32 4.36 � 0.04 1.80
*Outliers.
Table 70. Inhibition of binding of dextramethorphan to P450 2D6 by phenothiazines 4-X-7-OMe
coumarin analogs.
log1/C PRED DEV L�X
1 CH2NH2 3.88 3.54 0.34 4.02
2 CH2NHCH3 4.05 4.07 � 0.03 4.83
3 CH2NHC2H5 4.59 4.89 � 0.31 6.07
4 CH2NHC3H7 5.70 5.43 0.27 6.88
5 CH2NHC4H9 6.29 6.26 0.03 8.13
6 CH2N(CH3)2 3.77 4.07 � 0.31 4.83
QSAR of Cytochrome P450 143
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ORDER REPRINTS
pKi ¼ �0:37ð�0:24ÞC log P þ 0:026ð�0:017ÞNVE
þ 2:58ð�2:00Þ ð86Þ
n = 8, r2 = 0.885, s = 0.279, q2 = 0.715 outliers: Phenytoin, Tranylcypromine
It is surprising that NVE (sum of valence electrons) in each molecule is
important. Also unexpected is the negative Clog P term.
84. Binding of miscellaneous compounds to cytochrome P450 1A2 (Table 87).
Data from Lewis and Dickens (2001).
log 1=Km ¼ 4:49ð�1:10ÞMgVol � 2:18ð�1:67Þ ð87Þ
n = 8, r2 = 0.941, s = 0.194, q2 = 0.895
outliers: PHIP; 7-methoxyresorufin
Table 71. Conversion of P450 to P420 by phenols.
log1/C PRED DEV logP
1 3-NH2 0.46 0.46 0.0 0.17
2 3-OH 0.81 0.82 � 0.01 0.80
3 H 1.07 1.20 � 0.13 1.46
4 4-COOH 1.15 1.27 � 0.12 1.58
5 4-CH3 1.48 1.47 0.01 1.94
6 3-CH3 1.50 1.50 0.0 1.98
7 2-Cl 1.60 1.59 0.01 2.15
8 3-Et 1.82 1.74 0.08 2.40
9 4-Br 2.04 1.84 0.20 2.59
10 2-I 2.09 1.88 0.21 2.65
11 2,4-Cl 2.11 2.12 � 0.01 3.08
12 2,4,6-Cl 2.21 2.47 � 0.26 3.69
13 2.3,4,6-Cl 2.65 2.63 0.02 3.97
14* PENTA-Cl 2.90 3.23 � 0.33 5.01
*Outlier.
Table 72. Conversion of P450 to P420 by X–C6H4 –NH2.
log1/C PRED DEV logP
1 H 0.87 0.94 � 0.07 0.90
2 3-OH 0.46 0.45 0.01 0.17
3 4-F 1.12 1.10 0.02 1.15
4 4-CH3 1.30 1.26 0.04 1.39
5 3-CH3 1.31 1.27 0.04 1.40
6 2-Cl 1.48 1.60 � 0.12 1.90
7 3-Cl 1.68 1.59 0.09 1.88
144 Hansch et al.
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ORDER REPRINTS
85. Binding of miscellaneous compounds to cytochrome P450 2B6 (Table 88).
Data from Lewis and Dickens (2001).
log 1=Km ¼ 1:05ð�0:46ÞC log P þ 1:64ð�1:13Þ ð88Þ
n = 7, r2 = 0.872, s = 0.577, q2 = 0.760
outliers: Tetosterone, Benzphetamine, Bupropion
86. Binding of miscellaneous chemicals to cytochrome P450 2C9 (Table 89).
Data from Lewis and Dickens (2001).
log 1=Km ¼ 0:36ð�0:24ÞClogP þ 0:51ð�0:37ÞCMR
� 0:28ð�3:1Þð89Þ
n = 7, r2 = 0.860, s = 0.266, q2 = 0.681
outliers: Tienilic acid; 58C80; naproxen
87. Inhibition of cytochrome P450-CYP 2C9 (Table 90). Data from Lewis and
Dickens (2001).
pKi ¼ �0:57ð�0:18ÞCMR
þ 1:24ð�0:36Þbilin CMR 7:69ð�1:17Þ ð90Þ
n = 8, r2 = 0.958, s = 0.150, q2 = 0.858 outliers: omeprazole, fluconazole
Another example of an allosteric reaction.
Table 73. Dissociation of isotrole-metabolite P450 complex.
log1/C PRED DEV logP
1 H 0.87 0.94 � 0.07 0.90
2 3-OH 0.46 0.45 0.01 0.17
3 4-F 1.12 1.10 0.02 1.15
4 4-CH3 1.30 1.26 0.04 1.39
5 3-CH3 1.31 1.27 0.04 1.40
6 2-Cl 1.48 1.60 � 0.12 1.90
7 3-Cl 1.68 1.59 0.09 1.88
Table 74. Dissociation of X-C6H4-COOH P450 complex.
log Ks PRED DEV ClogP
1 C4H9 2.72 2.75 � 0.03 0.88
2 C5H11 3.03 3.06 � 0.03 1.41
3 C6H13 3.30 3.37 � 0.07 1.94
4 C7H15 3.77 3.67 0.10 2.47
5 C8H17 4.15 3.98 0.17 3.0
6 C10H21 4.46 4.59 � 0.13 4.06
QSAR of Cytochrome P450 145
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ORDER REPRINTS
Table 75. Dissociation of X–C6H4COOOH P450 complex.
logK2/K1 PRED DEV s ClogP
1 4-C3H7 � 0.85 � 0.89 0.04 � 0.13 2.12
2 4-Br � 0.36 � 0.36 0.0 0.23 1.53
3 4-C2H5 � 0.38 � 0.38 0.0 � 0.15 1.59
4 4-Cl � 0.24 � 0.21 � 0.03 0.23 1.38
5 3-Cl � 0.26 � 0.23 � 0.03 0.37 1.38
6 3-OC2H5 � 0.01 � 0.06 0.05 0.10 1.23
7 4-OC2H5 � 0.04 � 0.03 � 0.01 � 0.24 1.23
8 3-Me 0.04 0.12 � 0.08 � 0.07 1.07
9 4-Me 0.15 0.13 0.02 � 0.17 1.07
10 3-F 0.30 0.32 � 0.02 0.34 0.81
11 4-F 0.32 0.35 � 0.03 0.06 0.81
12 3-OMe 0.48 0.45 0.03 0.12 0.70
13 4-OMe 0.51 0.48 0.03 � 0.27 0.70
14 4-NO2 0.49 0.56 � 0.07 0.78 0.52
15 H 0.59 0.59 0.0 0.0 0.57
16 3-NO2 0.65 0.56 0.09 0.78 0.52
17 4-CN 0.86 0.85 0.01 0.66 0.23
Table 76. Dissociation of X–C6H5 –C(Me)2COOOH P450 complex.
log1/C PRED DEV PI s
1* 4-Br � 0.10 0.33 � 0.43 0.86 0.23
2 3-Br 0.18 0.25 � 0.07 0.86 0.39
3 3-Cl 0.40 0.38 0.02 0.71 0.37
4 3-Me 0.76 0.74 0.02 0.56 � 0.07
5 4-Me 0.74 0.79 � 0.05 0.56 � 0.17
6 3-F 0.89 0.87 0.02 0.14 0.34
7 4-F 1.0 1.02 � 0.02 0.14 0.06
8 4-NO2 1.11 0.98 0.13 � 0.28 0.78
9 3-NO2 1.04 1.02 0.02 � 0.28 0.71
10 4-CN 1.23 1.29 � 0.05 � 0.57 0.66
11 H 1.28 1.17 0.11 0.0 0.0
12 3-CN 1.20 1.34 � 0.13 � 0.57 0.56
*Outlier.
Table 77. Binding of aromatic hydrocarbons to P450.
logK2/K1 PRED DEV s ClogP
1 4-Cl 0.11 0.09 0.02 0.23 1.89
2 3-Me 0.52 0.49 0.03 � 0.07 1.68
3 4-Me 0.48 0.54 � 0.06 � 0.17 1.68
4 3-F 0.59 0.64 � 0.05 0.34 1.32
5 4-F 0.83 0.79 0.03 0.06 1.32
6 H 1.0 0.98 0.02 0.0 1.18
146 Hansch et al.
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ORDER REPRINTS
Table 81. Binding of Y–HNCHXCH2C6H5 to P450.
log Vmax/Km PRED DEV ES
1 H � 0.05 � 0.20 0.16 0.0
2 3,5-di–Me 1.36 1.11 0.26 � 2.48
3 3,5-di–C2H5 1.39 1.18 0.20 � 2.62
4* 3,5-di–C3H7 0.93 1.31 � 0.37 � 2.86
5 3,5-di–F 0.11 0.38 � 0.26 � 1.10
6 3,5-di–Cl 0.68 0.82 � 0.14 � 1.94
7 3,5-di–Br 0.93 1.02 � 0.09 � 2.32
8 3,5-di–I 1.39 1.51 � 0.12 � 3.24
*Outlier.
Table 80. Binding of 3,5-di-X-4-OH acetanilide to P450.
logKd PRED DEV ClogP ER
1 I 1.04 1.12 � 0.08 3.76 0.12
2 4-Me 1.87 1.74 0.12 3.14 0.03
3 4-Br 1.35 1.47 � 0.12 3.50 0.12
4 H 2.32 2.35 � 0.03 2.64 0.0
5 4-Cl 1.78 1.62 0.15 3.35 0.10
6 4-F 1.92 1.98 � 0.06 2.78 � 0.07
7* 4-CN 1.61 3.71 � 2.10 2.07 0.24
8* 4-N02 1.87 3.70 � 1.83 2.38 0.41
9 4-CHMe2 0.48 0.48 0.0 4.07 0.03
10 CMe3 � 0.04 � 0.06 0.02 4.47 0.03
*Outliers.
Table 79. Dissociation of 4-X-C6H4-Me from P450 2B4.
logKd PRED DEV s ClogP
1 I 1.26 1.18 0.08 0.18 3.76
2 4-Me 1.11 1.12 � 0.01 � 0.17 3.14
3 4-Br 1.06 1.01 0.05 0.23 3.50
4 H 0.88 0.73 0.15 0.0 2.64
5 4-Cl 0.79 0.93 � 0.14 0.23 3.35
6 4-F 0.61 0.76 � 0.14 0.06 2.78
7* 4-CN 0.32 � 0.08 0.39 0.66 2.07
8 4-N02 0.01 � 0.01 0.02 0.78 2.38
*Outlier.
Table 78. Dissociation from 4-X–C6H4Me to P450 2B4.
logKs PRED DEV logP
1 Benzene 3.15 3.14 0.01 2.13
2 Toluene 3.66 3.61 0.05 2.73
3 Butylbenzene 4.82 4.91 � 0.09 4.38
4 Ethylbenzene 3.71 3.94 � 0.23 3.15
5 Propylbenzene 4.64 4.39 0.25 3.72
QSAR of Cytochrome P450 147
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ORDER REPRINTS
DISCUSSION
First considering QSAR with positive log P terms, we find the following: 1, 2, 3, 4,
6, 11, 12, 13, 16, 17, 18, 19, 20, 22, 23, 24, 28, 29, 37, 38, 43, 47, 57, 63, 67, 71, 72,
77, 81, 82, 85, 88, and 89. That is, in all of these examples, more potent compounds
could have been made if the investigators had even the simplest understanding of
QSAR. The next question is what kind of upper limit occurs?
Table 82. Binding of X–C6H4N(Me)2 to P450.
X Y log Vmax PRED DEV ClogP I
1 CH3 H 0.20 0.56 � 0.36 1.74 1.0
2 C2H5 H 0.56 0.72 � 0.17 2.27 1.0
3 N-C3H7 H 0.89 0.88 0.01 2.80 1.0
4 N-C4H9 H 1.0 1.03 � 0.04 3.33 1.0
5 I-CH(Me)2 H 1.03 0.84 0.19 2.67 1.0
6 T-C(Me)3 H 1.01 0.96 0.05 3.07 1.0
7 I-CHCH2(Me)2 H 1.18 1.0 0.18 3.20 1.0
8 CH2C6H5 H 1.12 0.98 0.13 3.16 1.0
9 H OH 2.11 1.97 0.14 0.99 0.0
10 CH3 OH 2.27 2.06 0.21 1.30 0.0
11 Et OH 2.16 2.22 � 0.06 1.83 0.0
12 N-C3H7 OH 2.54 2.38 0.16 2.36 0.0
13 N-C4H9 OH 2.32 2.53 � 0.21 2.89 0.0
14 I-CH(Me)2 OH 2.35 2.34 0.01 2.23 0.0
15 T-C(Me)3 OH 2.12 2.46 � 0.34 2.63 0.0
16 I-CH2CH(Me)2 OH 2.55 2.46 0.09 2.63 0.0
Table 83. Binding of miscellaneous nitro compounds to P450.
log1/Km PRED DEV ClogP B1
1 H 4.57 4.40 0.17 2.31 1.0
2 Me 3.85 3.94 � 0.09 2.81 1.52
3 C2H5 3.52 3.62 � 0.10 3.34 1.52
4 (CH2)2CH3 3.15 3.18 � 0.03 3.86 1.52
5 CHMe2 3.02 3.11 � 0.09 3.73 1.90
6 (CH2)3CH3 2.68 2.62 0.06 4.39 1.52
7 CH2CHMe2 2.62 2.77 � 0.15 4.26 1.52
8 CH(Me)CH2CH3 2.52 2.58 � 0.06 4.26 1.90
9 CMe3 2.48 2.37 0.11 4.13 2.60
10 (CH2)2CHMe2 2.23 2.12 0.11 4.79 1.52
11 OMe 4.24 4.22 0.02 2.33 1.35
12 OC2H5 3.91 4.0 � 0.09 2.86 1.35
13 OCOMe 4.37 4.32 0.05 1.76 1.35
14 COOMe 4.18 3.98 0.20 2.59 1.64
15 NHCOMe 4.33 4.30 0.03 1.33 1.35
16 CH2NHCOMe 4.04 4.18 � 0.14 1.12 1.52
148 Hansch et al.
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ORDER REPRINTS
Table 84. NADPH–cytochrome P450 reductase action on miscellaneous aromatic
nitro compounds.
Log Kcat/Km PRED DEV E
1 Nifuroxim 4.79 4.95 � 0.16 � 0.26
2 Nitrofurantoin 4.79 4.83 � 0.05 � 0.27
3 4-Nitrobenzaldehyde 4.40 4.15 0.25 � 0.33
4 4-Nitroacetophenone 3.85 3.81 0.05 � 0.36
5 4-Nitrobenzoic acid 3.04 3.01 0.03 � 0.43
6 Nitrobenzene 2.20 2.32 � 0.12 � 0.49
Table 85. Binding of RNH2 to P450 2B1.
log Vmax/Km PRED DEV E
1 Nitrofurazone � 1.27 � 1.57 0.30 � 0.26
2 Nitrofurantoin � 2.0 � 1.67 � 0.33 � 0.26
3 Benznidazole � 3.14 � 3.43 0.29 � 0.38
4 P–Nitrobenzoate � 4.33 � 3.95 � 0.38 � 0.42
5 Metronidazole � 4.91 � 5.03 0.12 � 0.49
Table 86. Binding of miscellaneous drugs to P450 2C19.
pK1 PRED DEV ClogP
1 C3H7 0.39 0.39 0.0 1.94
2 C4H9 0.92 0.92 0.0 2.40
3* C5H11 1.45 1.45 0.0 2.87
4 C6H13 1.98 1.98 0.0 3.33
5 C7H26 2.51 2.51 0.0 3.79
6 C8H17 3.04 3.04 0.0 4.26
7 C10H21 4.10 4.10 0.0 5.18
8 C12H25 5.16 5.16 0.0 6.11
*Outlier.
Table 87. Binding of miscellaneous compounds to P450 1A2.
pKI PRED DEV ClogP NVE
1 S–Mephenytoin 4.22 4.04 0.19 2.0 84.0
2 Omeprazole 5.39 4.92 0.46 2.57 126.0
3 Propranolol 3.95 4.23 � 0.28 2.75 102.0
4 Diazepam 4.0 4.10 � 0.10 2.96 100.0
5 R–Warfarin 4.49 4.54 � 0.04 2.90 116.0
6* Phenytoin 3.55 4.27 � 0.71 2.09 94.0
7 Ly307640 5.04 5.26 � 0.23 2.08 132.0
8 Fluconazole 5.70 5.73 � 0.03 � 0.44 114.0
9* Tranylcypromine 5.10 3.39 1.70 1.48 52.0
10 Desmethyldiazepam 3.94 3.92 0.02 3.02 94.0
*Outliers.
QSAR of Cytochrome P450 149
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ORDER REPRINTS
There are six QSAR that define the optimum log P either by having a log P2 term
or a bilinear log P term. The set numbers and optimal log P are as follows:
Set #s Optimum log P Type of P450
1. 38 5.24 Rat liver
2. 44 1.53 BM-3 from bacillus megaterium
3. 60 5.60 P450 2C9 expressed in yeast microsomes
4. 82 1.64 Rabbit P450
This gives one a rough idea in planning new congeners. Of course, the real enigma
with understanding P450 metabolism is that we have no in vivo studies for comparison.
It is well known that optimum log P values are higher for in vitro studies than for in
vivo work.
Table 88. Binding of miscellaneous compounds to P450 2B6.
log1/Km PRED DEV MgVol
1 Caffeine 3.74 3.94 � 0.20 1.36
2* Phip 4.26 5.51 � 1.25 1.71
3* 7-Methoxyresorufin 6.68 4.96 1.72 1.59
4 Phenacetin 4.32 4.35 � 0.03 1.45
5 Iq 4.48 4.44 0.04 1.47
6 Meiq 4.89 5.07 � 0.19 1.61
7 4-Aminobiphenyl 4.52 4.21 0.31 1.42
8 7-Ethoxyresorufin 5.77 5.59 0.18 1.73
9 Theophylline 3.34 3.31 0.03 1.22
10 Tacrine 4.85 5.0 � 0.15 1.60
*Outliers.
Table 89. Binding of miscellaneous compounds to P450 2C9.
log1/Km PRED DEV ClogP
1 7-Benzyloxyresorufin 5.89 5.46 0.43 3.64
2 4-Trifluromethyl–7-Ethoxycoumarin 5.54 4.98 0.55 3.18
3* Testosterone 4.30 5.23 � 0.93 3.41
4* Benzphetamine 4.03 6.25 � 2.22 4.38
5 7-Ethoxycoumarin 3.94 4.03 � 0.09 2.27
6 Diazepam 3.95 4.75 � 0.81 2.96
7* Bupropion 3.97 5.02 � 1.05 3.21
8 Mephenytoin 3.25 3.74 � 0.49 2.0
9 Sm-12502 2.75 2.24 0.51 0.57
10 Antipyrine 1.75 1.85 � 0.10 0.20
*Outliers.
150 Hansch et al.
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ORDER REPRINTS
There are a number of examples where a negative log P term is found: 7, 10, 21,
27, 32, 35, 46, 51, 61, 75, 76, 78, 79, and 86. These 14 examples need special
consideration. Three of these examples (73, 78, 79) are studies on dissociation of a
complex. Knowing that log P is normally positive for association, negative values for
dissociation are to be expected. It is not clear why QSAR 46 and 51 have negative log
P terms. Examples 7, 10, 27, and 32 pertain to oxidation reduction studies, assuming
that dehalogenation falls into this mode. Of course, in considering these terms, the
coefficients vary considerably. These values will depend on the size of the hydrophobic
site of the receptor and the size of the ligand.
There are a number of examples where the QSAR contain Hammett electronic
parameters [5, 8 +, 9, 11, 14, 15, 18 +, 19 +, 20 +, 25(HOMO) 26, 29, 46, 51, 53, 74,
75]. All of the examples except the four marked with +, have negative coefficients,
indicating that substituent release of the electrons to central structure increases potency.
The one example based on HOMO also points in this direction. Examples 19, 20, and
21 are for the oxidation of benzyl alcohols, where electron withdrawal would make
removal of H from the methylene group easier. Example 8 is somewhat like that of the
benzyl alcohols in that a hydrogen is being removed from a dialkyl amine moiety. The
coefficients in all of these examples are very small and of very little importance in
drug design.
Another type of electronic interaction that has been almost completely neglected
is that of electron polarizability. We discovered two ways of dealing with this prob-
lem (62). The most important is that based on the Lorentz–Lorenz equation:
MR = (n2 � 1/n2 + 2) (MW/d ) MR = molecular polarizability. In this expression,
n = refractive index, MW = molecular weight, and d = density. Many years ago, Leo
developed an algorithm for its calculation (CMR). We now have 1,701 QSAR based on
this parameter. One must take into account the interactions of the electrons in the
ligand and receptor. Of course, MW/d is a volume term that is important.
Another way to deal with polarizability is to use the sum of the valence electrons
in a molecule (NVE) (Hansch et al., 2003). We now have 607 QSAR based on this
parameter. In the present study, we find only two examples (34, 86) based on NVE and
10 QSAR with CMR (15, 48, 58, 61, 62, 64, 66, 89).
Table 90. Binding of miscellaneous compounds to CYP 2C19.
log1/Km PRED DEV ClogP CMR
1 Phenytoin 4.35 4.11 0.23 2.09 7.22
2 Tolbutamide 3.88 4.21 � 0.33 2.50 7.12
3 Ibuprofen 4.28 4.13 0.16 3.68 6.12
4 Diclofenac 5.22 5.28 � 0.06 4.73 7.67
5 Warfarin 5.40 5.16 0.24 2.90 8.72
6* Tienilic acid 5.22 4.79 0.43 3.23 7.76
7* 58c80 3.85 6.37 � 2.52 6.08 8.87
8* Naproxen 3.90 4.05 � 0.15 2.82 6.57
9 Piroxicam 4.40 4.58 � 0.18 1.89 8.29
10 Mefenamic acid 5.15 5.22 � 0.06 5.29 7.15
*Outliers.
QSAR of Cytochrome P450 151
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ORDER REPRINTS
It is possible that electronic interactions are not significant, and activity is
associated with change in ligand volume. In this review, we find such examples (33,
41, 49, 52, 65, 87). In our database, we have 717 QSAR with a volume term (MgVol).
A chemical–biological interaction of importance is that of allosteric interactions
(59, 64, 65) (55). Not that with these QSAR there is a negative linear term that shows
as the parameter concerned increases in size and activity declines, however, as the
exponential term increases in size, activity begins to increase. That is, one has an
inverted parabolic relationship. This is due to a change in shape of the enzyme. It is
interesting to find that such a reaction can occur with some P450 enzymes. Steric
parameters are important for the development of rational QSAR. The so-called sterimol
parameters are most useful. These were developed by Verloop and were discussed by
us (Lewis et al., 2001, pp. 76–78). Although there were originally five, it was decided
that only three were of real value: B1, B5, and L. B1 accounts for the steric effect of
the first atom in a substituent. B5 is an attempt to define the maximum width, and L is
for substituent length. In the present study, we found 5 QSAR with B1 (6, 45, 50, 55,
56); 5 with B5 (13, 45, 46, 68, 69), and 6 with L (30, 31, 40, 54, 55, 70).
The first steric parameter, Es, was designed by Taft mainly for physical organic
chemistry, nevertheless, we found it to be of use in chemical–biological interactions.
The following summary indicates the number of QSAR in our current biological
database for the steric parameters: B1 (1019); B5 (891); L (838); and ES (320).
Because we found rather few instances where steric parameters are important in the
QSAR of P450 enzymes, this would suggest a relatively large and flexible active site.
We believe our review sheds some light on the role of P450 enzymes in absorption,
distribution, metabolism, and elimination. There are 39 QSAR with positive hydrophobic
terms for the oxidation of a wide variety of compounds. The overall picture is that
hydrophobic drugs are attractive targets for P450 enzymes. Also, we have limited data
that indicates hydrophobic compounds induce the formation of P450. Hence, it would
seem that one should search for hydrophilic compounds as drug candidates.
All of our studies are for in vitro work, but what is really needed are some in vivo
studies. Using the information obtained in this report, it should be possible to obtain a
deeper understanding of M (metabolism) in ADME.
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