Discovery of 4-(5-methyloxazolo[4,5-b]pyridin-2-yl)-1,4-diazabicyclo[3.2.2]nonane (CP-810,123), a novel alpha 7 nicotinic acetylcholine receptor agonist for the treatment of cognitive disorders in schizophrenia: synthesis, SAR development, and in vivo efficacy in cognition models

Christopher J O'Donnell; Bruce N Rogers; Brian S Bronk; Dianne K Bryce; Jotham W Coe; Karen K Cook; Allen J Duplantier; Edelweiss Evrard; Mihaly Hajós; William E Hoffmann; Raymond S Hurst; Noha Maklad; Robert J Mather; Stafford McLean; Frank M Nedza; Brian T O'Neill; Langu Peng; Weimin Qian; Melinda M Rottas; Steven B Sands; Anne W Schmidt; Alka V Shrikhande; Douglas K Spracklin; Diane F Wong; Andy Zhang; Lei Zhang

doi:10.1021/jm9015075

Discovery of 4-(5-methyloxazolo[4,5-b]pyridin-2-yl)-1,4-diazabicyclo[3.2.2]nonane (CP-810,123), a novel alpha 7 nicotinic acetylcholine receptor agonist for the treatment of cognitive disorders in schizophrenia: synthesis, SAR development, and in vivo efficacy in cognition models

J Med Chem. 2010 Feb 11;53(3):1222-37. doi: 10.1021/jm9015075.

Affiliation

¹ Pfizer Global Research and Development, Groton Laboratories, Eastern Point Road, Groton, Connecticut 06340, USA. christopher.j.odonnell@pfizer.com

PMID: 20043678
DOI: 10.1021/jm9015075

Abstract

A novel alpha 7 nAChR agonist, 4-(5-methyloxazolo[4,5-b]pyridin-2-yl)-1,4-diazabicyclo[3.2.2]nonane (24, CP-810,123), has been identified as a potential treatment for cognitive deficits associated with psychiatric or neurological conditions including schizophrenia and Alzheimer's disease. Compound 24 is a potent and selective compound with excellent pharmaceutical properties. In rodent, the compound displays high oral bioavailability and excellent brain penetration affording high levels of receptor occupancy and in vivo efficacy in auditory sensory gating and novel object recognition. The structural diversity of this compound and its preclinical in vitro and in vivo package support the hypothesis that alpha 7 nAChR agonists may have potential as a pharmacotherapy for the treatment of cognitive deficits in schizophrenia.

MeSH terms

Animals
Azabicyclo Compounds / chemical synthesis*
Azabicyclo Compounds / chemistry
Azabicyclo Compounds / pharmacology*
Biological Availability
Cells, Cultured
Cognition Disorders / drug therapy*
Epithelial Cells / drug effects
Female
Hippocampus / drug effects
Humans
Kidney / cytology
Kidney / drug effects
Microsomes, Liver / drug effects
Nicotinic Agonists / chemical synthesis*
Nicotinic Agonists / chemistry
Nicotinic Agonists / pharmacology*
Nootropic Agents / chemical synthesis*
Nootropic Agents / chemistry
Nootropic Agents / pharmacology*
Oocytes / drug effects
Oxazoles / chemical synthesis*
Oxazoles / chemistry
Oxazoles / pharmacology*
Rats
Receptors, Nicotinic / chemistry*
Schizophrenia / drug therapy*
Skin / cytology
Skin / drug effects
Structure-Activity Relationship
Xenopus laevis / growth & development
alpha7 Nicotinic Acetylcholine Receptor

Substances

4-(5-methyloxazolo(4,5-b)pyridin-2-yl)-1,4-diazabicyclo(3.2.2)nonane
Azabicyclo Compounds
Chrna7 protein, human
Chrna7 protein, rat
Nicotinic Agonists
Nootropic Agents
Oxazoles
Receptors, Nicotinic
alpha7 Nicotinic Acetylcholine Receptor