Discovery of 4-(5-Methyloxazolo[4,5-b]pyridin-2-yl)-1,4-diazabicyclo[3.2.2]nonane (CP-810,123), a Novel alpha7 Nicotinic Acetylcholine Receptor Agonist for the Treatment of Cognitive Disorders in Schizophrenia: Synthesis, SAR Development, and in Vivo Efficacy in Cognition Models.

Journal of medicinal chemistry 2009 Dec 31; In press

O'donnell C CJ, Rogers B BN, Bronk B BS, Bryce D DK, Coe J JW, Cook K KK, Duplantier A AJ, Evrard E, Hajós M, Hoffmann W WE, Hurst R RS, Maklad N, Mather R RJ, McLean S, Nedza F FM, O'Neill B BT, Peng L, Qian W, Rottas M MM, Sands S SB, Schmidt A AW, Shrikhande A AV, Spracklin D DK, Wong D DF, Zhang A, Zhang L

Pfizer Global Research and Development, Groton Laboratories, Eastern Point Road, Groton, Connecticut 06340.

A novel alpha7 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 alpha7 nAChR agonists may have potential as a pharmacotherapy for the treatment of cognitive deficits in schizophrenia.

Keywords: Nicotinic alpha7 Nicotinic Cognitive Schizophrenia Cognition