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KJM5230-H06
Drug Design:Functional groups / Pharmacological Activity
Structure - Mechanism of action (Interaction with target)
Structure - Physiochemical properties (Bioavailability etc)• Acid / base properties• Water solubility• Partition coefficient• (Crystal structure)• Stereochemistry
ADME
Absorbtion. Distribution, Metabolism, Excretion(ADMET, ADMEtox)
KJM5230-H06
Structure - Mechanism of action
NO
O
OH
ca. 5Å
Acetylcholin (Neurotransmittor)
NO
O
H2N
Carbacholin
N
NH
N
NMe
H
OO
Acetylcholin Agonists
Nicotine Pilocarpine
Protonated av phys. pH (pH≈7.4)
Acetylcholin Antagonists
N
O
O
OH
Atropin
O
O
N
OH
Cyclopentolat
MeO
O
HO
OOH
OMe
NH
Me
NMe
Me
TubocurarinCNS
Effektor celle
Reseptor
Synapse
Acetylkolin
Noradrenalin
Det somatiske nervesystem Det autonome nervesystem
CNS CNS
Det sympatiskenervesystem
Det parasympatiskenervesystem
ganglion
KJM5230-H06
Structure - Mechanism of action
SAR: Structure Activity Relationships
Acetylcholine agonists: Small N-quartenary compds.Acetylcholine antagonists: Larger N-quartenary compds.
NCO2Me
O
OCocaine
O
O
N
NH2
Procaine (1905)
NH
N
Lidocaine/Xylocaine(1946)
O
Acid labile ester
HydrophilicAminogroup(can be protonated)
Spacer-Cn-X-X: -CO2- -CONH- -NHCO-
Lipophilic(Aryl)
N
N N
N
R
O
MIC (μg/mL )
R
-H
-CH3
-CH2CH=CH2
-CH2Ph
-SO2Ph
-CH(CH3)Ph
-Ph
-CH2CH2Ph
% Inhibition M. tuberculosis 6.25 μg/mL
6
0
7
>90 3.13
26
12.5
13
14
>90
KJM5230-H06
Structure - Physiochemical properties
• Acid / base properties• Water solubility• Partition coefficient• (Crystal structure)• Stereochemistry
Human body: ca 75% waterpH blood ca 7.4 (physiolog. pH)pH stomach 1 - 3.5pH duodenum ca. 4pH urine ca. 6
Identification of acidic / basic functional groups
pKa determines degree of ionization different places in the body
KJM5230-H06
NO
O
OH
ca. 5Å
Acetylcholin (Neurotransmittor)
Acetylcholin Antagonists Possible atropine analogs?
O
O
N
OH
Cyclopentolat
O
O
N
OHO
O
N
OHO
O
N
OH
O
Cyclopentolate - tertiary amine, pKa ca. 10
[acid form]
[base form]
At pH 7.4
10 = 7.4 + log log[acid form]
[base form]= 2.6
[acid form]
[base form]= 398; 99.75% acid form
O
O
N
OHH = active form
O
O
N
OHH
acid form
+ H20O
O
N
OH
baseform
+ H3O
pKa = pH + log[acid form]
[base form]Henderson Hasselbach
pH=pKa; [acid]= [base]pH<pKa; acid form dominatespH>pKa; basic form dominates
KJM5230-H06
Antibacterial sulfonamides
Old compound
NH2SO
OH2N
Acid form - neutralLow watersol. - crystals - Kidney damage
[acid form]
[base form]
At pH 6 (urine)
10.4 = 6 + log[acid form]
[base form]≈ 25000
Modern compound
ArS
O
O
HN
Sulfametoksasol
pKa 6.1
ArS
O
O
N
- H
+
ArS
O
O
NArS
O
O
N
N
O
N
O
N
O
N
O
ArS
O
O
N
N
O
At pH 6 (urine)
[acid form]
[base form]≈ 1
base form, ionic, water sol.
KJM5230-H06
Structure - Physiochemical properties• Acid / base properties• Water solubility• Partition coefficient• (Crystal structure)• Stereochemistry
Ionisation -permanent charge -acid / base properties
Hydrogen bonds
Ion - dipole bonds
H
N HR
H
Acidic form of amines
H
OH
δ -
δ +
δ +
R
O
O
Basic form of carboxylic acid(carboxylate)
HO
Hδ +
δ + δ -
Intramoleculare interact. reduce water sol.
R
CO2
NH3
Strong intramolec interact.
OH H
OHH
Salts between weak organic acids and weak organic bases does not dissolve well in water
KJM5230-H06
The more H-bonds possible - the more water sol.
RO
HAlchohol
O
HH
H
OH
OH
H
3 H-Bonds
OAldehyde / ketone
HH
OH
OH
2 H-Bonds
R R'
OEster
HH
OH
OH
3 H-Bonds
R OR
HO
H
Primary amine 3 H-BondsR N
H
H
O
O
HO
H
H
H
HH
Secondary amine 2 H-BondsR N
R'
H O
HO
H
H
H
Secondary amine 1 H-BondsR N
R'
R''
HO
H
KJM5230-H06
Prediction of water solubility - Empirical
Water solubilization of functional groups
Functional group Monofunctional comp. Polyfunctional
comp.
Alchohol 5 – 6 carbons 3 – 4 carbons
Phenol 6 – 7 3 – 4
Ether 4 – 5 2
Aldehyde 4 – 5 2
Ketone 5 – 6 2
Amine 6 – 7 3
Carboxylic acid 5 – 6 3
Ester 6 3
Amide 6 2 - 3
Ex. monofuctional comp.methanol - pentanol/hexanol are solubile
Charge: 1 charge - 20-30 C
N
TerbinafineAntifungal agent
21 C-atom, tertiary amine solubilize 6 - 7 C atoms
Insolubile (neutral form)
Corresponding acid (cationic) solubile
(solubile: >10 mg/mL)
KJM5230-H06
Water solubilization of functional groups
Functional group Monofunctional comp. Polyfunctional
comp.
Alchohol 5 – 6 carbons 3 – 4 carbons
Phenol 6 – 7 3 – 4
Ether 4 – 5 2
Aldehyde 4 – 5 2
Ketone 5 – 6 2
Amine 6 – 7 3
Carboxylic acid 5 – 6 3
Ester 6 3
Amide 6 2 - 3
Ex. polyfunctional comp.
Charge: 1 charge - 20-30 C
O
O
NH
OH
BetaxololBetablokker
18 C-atomer
Ether: 2
Ether: 2
Alchohol: 3-4
Amine 2
Tot: 9 - 10
(not solubile)
KJM5230-H06
logP
Experimental: MlogP or logPmeas
P: Partition coefficient between n-octanol and water
Fragment π-value
C (aliphatic +0.5
Phenyl +2.0
-Cl +0.5
-ONO2 +0.2
-S- 0.0
=O C-O- (carboxyl) -0.7
=O C-N- (amide) -0.7
- -O (hydr , oxyl ether) -1.0
N (amine) -1.0
-NO2 (alipha .)t -0.85
-NO2 (aroma .t ) -0.28
O
O
NH
OH
BetaxololBetablokker
12 x C aliphat: +6.0
Ph: +2.0
3 x O: -3.0
N: -1.0
logP +4.0
ClogP (SciFinder): 2.69
π-value: hydrophilic - lipophilic value
logP Rt (HPLC, TLC reverse phease)
Structure - Physiochemical properties• Acid / base properties• Water solubility• Partition coefficient• (Crystal structure)• Stereochemistry
Calcd: ClogP
KJM5230-H06
Absorbtion of Bioactive Compounds
Absorbtion from GI tract
StomachpH 1-3
DuodenumpH 5-7
Jejunum
IleumpH 7- 8
Small intestine
+ digestive enzymes
Drug
GI-tractBlood
Membrane
Acidic / Enzymatic break down
Often rate limiting
Binding to biomolecules
KJM5230-H06
Most drugs: Passive diffusion
StomachpH 1 - 3
Blood
Lipophilic Membrane
R-H R-H
R-CO2H R-CO2H
R-NH3
Amount un ionized drug
pKa pH
pKa = pH + log[acid form]
[base form]Henderson Hasselbach
Low lipophilicity unionized form - low absorbtion
logP - P: Partition coefficient between n-octanol and water Water phase - extracellular fluid
Lipophilic phase - cell membrane
KJM5230-H06
Crossing the membrane
High conc.
Low conc.Chanel protein
Passive transport / diffusion
Rate Conc. absortion site (1. order kinetics)% Drug absorbed lipophilicity
Size of molecule
Certain ionic compounds may go thru as ion-pair
KJM5230-H06
Active transport / Carrier mediated transport
•Less common
•Structural recemblanse with for instance nutritional compound
•Transport against conc. gradient
•Mechanism saturated at high conc.
•Competition for carrier molecules, compounds with structural resemblance
Energy
KJM5230-H06
The Lipinski "Rule of Five"
states that compounds are likely to have good absorption and permeation in biological systems and are more likely to be successful drug candidates if they meet the following criteria:
five or fewer hydrogen-bond donors
ten (2 x 5) or fewer hydrogen-bond acceptors
molecular weight less than or equal to 500
calculated logP less than or equal to 5
*Compound classes that are substrates for biological transporters are exceptions to the rule.
Not too polar
Not too big
Not too hydrophobic
KJM5230-H06
Biomolecules (reseptors, enzymes): AsymmetricEnantiomers may behave differently:
•Absorbtion (membrane selectivity)
•Metabolism
•Binding to other reseptors than target
(loss, side effects)
•Binding to target reseptor
Structure - Physiochemical properties• Acid / base properties• Water solubility• Partition coefficient• (Crystal structure)• Stereochemistry
A
BC
D
Drug
Biomolecular target
Desired responce
D
BC
A
No desired resonceSide effects??
KJM5230-H06
Restricted rotation - optically active rotamers
P
P
(R)-(+)-BINAP
P
P
(S)-(-)-BINAP
I I
I
NH2
O
CO2H*
Chiral C-atom
Chiral axis (restrict. tot.)4 stereoisomers
X-ray contrast agent
KJM5230-H06
•Screening/Design/Serendipity/Natural products •Lead compound
•Structure Optimisation•Actual Drug
Refinement of lead structure:•Determining pharmacophore•Functional group modification
Pharmacophore: The part of the molecule that contains the functional groups that actually binds to the reseptor
Morfin
O
OHN
OH
N
O
O
Petidine
N
O
O
Dextropropoxyphene
KJM5230-H06
N
N N
N
O
Cl
Lead compoundN
N N
N
Ar
X
Y
Z
Rel high activity
N
N N
N
O
R
R ≠ CH2Ph
N
N N
N
R
R=H, alkyl
Inactive
N
N N
N
Ar
Pharmacophore??
Azapurines??
Deazapurines?? N
N N
Ar
R
??
N
N
Ar
??
Antimycobacterials
??
X
Ar
KJM5230-H06
Improvement of lead by functional group modification
•Activity•Toxicity•Bioavailability•Metabolism
Isosters:Functional groups that results in approx. the same propertiesSteric and electronic similarities
S
bp 81 oC bp 84 oC
-CH=CH- and -S- are isosters
N
bp 116 oC
-C= and -N= not isosters
(at least with respect to bp)
KJM5230-H06
Bioisosters:Functional groups that results in approx. the same biological properties
Classical bioisostersSteric and electronic similarities
Monovalent-F, -H-OH, -NH2
-H, -F, -OH, -NH2, -CH3
-SH, -OH-Cl, -Br, -CF3
Divalent-C=S, -C=O, -C=NH, -C=C-
Trivalente-CH=, -N=
Tetravalente
Rings
N S O
N C
KJM5230-H06
N
N N
N
O
X
-X π σp % Inhib at6.25 μg/mL
MIC(μg/mL )
-H 0 0 >90 3.13-F 0.15 0.06 >90 6.25-OH -0.61 -0.37 79 n. .d-NH2 -1.23 -0.66 23 n. .d-CH3 0.60 -0.17 >90 3.13Bioisosters
σ: electronic effects; σ>0 electr on withdrawi ,ng σ<0 electr on donatingπ: Lipophilicity, π>0 incre asedlipophil. re l t o H
Non-classical bioisostersNot strong steric or electronic similarities
N
N
NNHO
O
N
N
NN
NH
N
O
HO2C
Angiotensin II antagonists(Hypertention)
N
NH
pKa 14.2
N
N
NH
pKa 9.2
N
N
NH
pKa 10.3
N
NN
NH
pKa 4.9 ≈ karboksylsyrer