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.
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.
O'Donnell
Christopher J
CJ
Pfizer Global Research and Development, Groton Laboratories, Eastern Point Road, Groton, Connecticut 06340, USA. christopher.j.odonnell@pfizer.com
Rogers
Bruce N
BN
Bronk
Brian S
BS
Bryce
Dianne K
DK
Coe
Jotham W
JW
Cook
Karen K
KK
Duplantier
Allen J
AJ
Evrard
Edelweiss
E
Hajós
Mihaly
M
Hoffmann
William E
WE
Hurst
Raymond S
RS
Maklad
Noha
N
Mather
Robert J
RJ
McLean
Stafford
S
Nedza
Frank M
FM
O'Neill
Brian T
BT
Peng
Langu
L
Qian
Weimin
W
Rottas
Melinda M
MM
Sands
Steven B
SB
Schmidt
Anne W
AW
Shrikhande
Alka V
AV
Spracklin
Douglas K
DK
Wong
Diane F
DF
Zhang
Andy
A
Zhang
Lei
L
D000818:Animals; D053961:Azabicyclo Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D001682:Biological Availability; D002478:Cells, Cultured; D003072:Cognition Disorders / Q000188:drug therapy*; D004847:Epithelial Cells / Q000187:drug effects; D005260:Female; D006624:Hippocampus / Q000187:drug effects; D006801:Humans; D007668:Kidney / Q000166:cytology / Q000187:drug effects; D008862:Microsomes, Liver / Q000187:drug effects; D018722:Nicotinic Agonists / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D018697:Nootropic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D009865:Oocytes / Q000187:drug effects; D010080:Oxazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D011978:Receptors, Nicotinic / Q000737:chemistry*; D012559:Schizophrenia / Q000188:drug therapy*; D012867:Skin / Q000166:cytology / Q000187:drug effects; D013329:Structure-Activity Relationship; D014982:Xenopus laevis / Q000254:growth & development; D064569:alpha7 Nicotinic Acetylcholine Receptor
C547674:4-(5-methyloxazolo(4,5-b)pyridin-2-yl)-1,4-diazabicyclo(3.2.2)nonane; D053961:Azabicyclo Compounds; C579167:Chrna7 protein, human; C579165:Chrna7 protein, rat; D018722:Nicotinic Agonists; D018697:Nootropic Agents; D010080:Oxazoles; D011978:Receptors, Nicotinic; D064569:alpha7 Nicotinic Acetylcholine Receptor