Synthesis and biological evaluation of fluorinated imidazo[1,2-a]pyridine derivatives as potential...
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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
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
human liver microsomes
human liver microsomes
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