Download pdf - Synthesis and biological evaluation of fluorinated imidazo[1,2-a]pyridine derivatives as potential antipsychotic agents

Marcinkowska, M.,1 Kamiński, K.,1 Bucki, A.,1 Pawłowski, M.,1 Wesołowska, A.,1 Kazek, G.,1 Siwek, A.,1 Kubowicz, P.,1 Pękala, E.,1 Mierzejewski, P.,2 Bieńkowski, P.2 and Kołaczkowski, M.,1,3

Synthesis and biological evaluation of fluorinated imidazo[1,2-a]pyridine derivatives as potential antipsychotic agents

1Jagiellonian University, Medical College, Cracow, Poland; 2Institute of Psychiatry and Neurology, Warsaw, Poland. 3Adamed Ltd., Pieńków, Poland [email protected], [email protected]

Studies were financed by National Science Center Poland (NCN), project nr: 5887/B/P01/2011/40; ‘Evaluation of antipsychotic properties of GABA-A receptor ligands; discovery of novel selective GABA-A receptor ligands with antipsychotic properties’

References

Introduction Zolpidem-liver metabolism

Design of fluorinated Zolpidem analogues

Currently available antipsychotics:

•  1. Typical antipsychotics (dopamine D2 receptor antagonists)- I generation

•  2. Atypical antipsychotics (act via wide range of receptors including serotonin 5-HT2Areceptors or D2 receptors)- II generation

•  They all cause many SIDE EFFECTS •  30-40% patients develop DRUG RESISTANCE

GABAergic drugs in psychotic disorders

Zolpidem as potential antipsychotic

In vitro affinity of novel molecules

Summary

[1] Paton, C. et al., J Clin Psychopharm, 2007,27,198-204 [2] Wong, M. Y. G., Bastiampillai, T., Dhillon, R., Aust N Z J Psychiatry 2010, 44, 190-195 [3] Mierzejewski, P. Neurosci Lett. 2013, 556, 99-103 [4] Dang, A., Garg, A. & Rataboli, P. V. Cns Neurosci. Ther. 2011, 17, 387–397 [5] Shimizu, H. et al Bioorg. Med. Chem. Lett. 2011, 21, 4550-4555

There is a need to search for a new antipsychotic drugs with a different mechanism of

action1

•  Approximately 50% patients treated with

GABAergic drugs experienced a significant improvement2

•  Recently, our research group has confirmed

specific antipsychotic properties of zolpidem, while testing different GABAergic drugs in animal model of psychosis3

GABAergic drug Amfetamine induced

hyperlocomotion

MK-801 induced hyperlocomotion

Diazepam n.a. n.a. Midazolam n.a. n.a. Alprazolam n.a. n.a. ZOLPIDEM 0.3 mg/kg 0.3 mg/kg Zopiklon n.a. n.a. Estazolam n.a. n.a.

•  Only Zolpidem showed antipsychotic effect (0.3mg/kg)

•  No sedative effect observed

q Dif ferent mechanism of act ion

comparing to currently available antipsychotics;

q  Zolpidem is a GABA-A receptor positive allosteric modulator

Desired

q  Fast liver metabolism q  Short t0,5= 2-3h

Weak points

Liver metabolism need to be improved

Fast elimination and half time of about 2-3h4

Blocking metabolic hotspots

Incorporation of fluorine5: -  provides analogs with increased metabolic stability due to

strength of C-F bond -  reduction of cytochrome P450 oxidative metabolism

New series of fluorinated imidazo[1,2-a]pyridine derivatives

In vitro GABA-A receptor benzodiazepine site affinity data

In vitro biotransformation study of the most active compounds

N

N

N

O

F

F

N

N

N

O

F

MK01

JW16

human liver microsomes


No metabolites

No metabolites

MK01 and JW16- metabolically stable fluorinated analogues

MK-‐1

JW-‐16

Compound MM-79 displayed higher affinity for GABA-A receptors than zolpidem and compounds MK-1 and JW-16 showed comparable activity

to the parent compound.

Compound Ki (nM) MM-‐79 24,6 Zolpidem 43,8 MK-‐1 45,6 JW-‐16 47,5 MK-‐3 85,6

MM-‐110 98 MM-‐124 127 MM-‐96 143,2 MM-‐042 177 MM-‐123 487 MM-‐111 827 MK-‐10 n.a. MK-‐4 n.a.

MM-‐113 n.a. MM-‐119 n.a. MK-‐7 n.a. MK-‐5 n.a.

MM-‐114 n.a.

Zolpidem (reference)

MM-‐79

N

N

N

O

F

F

N

N

N

O

F

MK01

JW16



After 60 min hydroxylation occurred- MM-79 is not stable

(GABA-A) Ki= 45,6 [nM]

(GABA-A) Ki= 47,5 [nM]

We obtain - metabolically stable fluorinated analogues of Zolpidem with comparable affinity to parent compound

Zolpidem

(GABA-A) Ki=43,8 [nM]

MK-1

JW-16

Metabolically unstable

Metabolically stable