Discovery of N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]furo[2,3-c]pyridine-5-carboxamide, an agonist of the alpha7 nicotinic acetylcholine receptor, for the potential treatment of cognitive deficits in schizophrenia: synthesis and structure--activity relationship.
N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]furo[2,3-c]pyridine-5-carboxamide (14, PHA-543,613), a novel agonist of the alpha7 neuronal nicotinic acetylcholine receptor (alpha7 nAChR), has been identified as a potential treatment of cognitive deficits in schizophrenia. Compound 14 is a potent and selective alpha7 nAChR agonist with an excellent in vitro profile. The compound is characterized by rapid brain penetration and high oral bioavailability in rat and demonstrates in vivo efficacy in auditory sensory gating and, in an in vivo model to assess cognitive performance, novel object recognition.
Wishka
Donn G
DG
Pfizer Global Research & Development, Eastern Point Road, Groton, Connecticut 06340, USA.
Walker
Daniel P
DP
Yates
Karen M
KM
Reitz
Steven C
SC
Jia
Shaojuan
S
Myers
Jason K
JK
Olson
Kirk L
KL
Jacobsen
E Jon
EJ
Wolfe
Mark L
ML
Groppi
Vincent E
VE
Hanchar
Alexander J
AJ
Thornburgh
Bruce A
BA
Cortes-Burgos
Luz A
LA
Wong
Erik H F
EH
Staton
Brian A
BA
Raub
Thomas J
TJ
Higdon
Nicole R
NR
Wall
Theron M
TM
Hurst
Raymond S
RS
Walters
Rodney R
RR
Hoffmann
William E
WE
Hajos
Mihaly
M
Franklin
Stanley
S
Carey
Galen
G
Gold
Lisa H
LH
Cook
Karen K
KK
Sands
Steven B
SB
Zhao
Sabrina X
SX
Soglia
John R
JR
Kalgutkar
Amit S
AS
Arneric
Stephen P
SP
Rogers
Bruce N
BN
D000818:Animals; D001682:Biological Availability; D001921:Brain / Q000378:metabolism; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D003072:Cognition Disorders / Q000188:drug therapy*; D004355:Drug Stability; D051638:Ether-A-Go-Go Potassium Channels / Q000187:drug effects; D005072:Evoked Potentials, Auditory / Q000187:drug effects; D006801:Humans; D066298:In Vitro Techniques; D007858:Learning / Q000187:drug effects; D008297:Male; D008568:Memory / Q000187:drug effects; D008862:Microsomes, Liver / Q000187:drug effects / Q000378:metabolism; D009474:Neurons / Q000187:drug effects / Q000502:physiology; D018722:Nicotinic Agonists / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D018697:Nootropic Agents / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D018408:Patch-Clamp Techniques; D011812:Quinuclidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011869:Radioligand Assay; D051381:Rats; D017207:Rats, Sprague-Dawley; D011978:Receptors, Nicotinic / Q000378:metabolism* / Q000502:physiology; D021641:Recognition, Psychology / Q000187:drug effects; D012559:Schizophrenia / Q000188:drug therapy*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D064569:alpha7 Nicotinic Acetylcholine Receptor
D019086:Bridged Bicyclo Compounds, Heterocyclic; C579167:Chrna7 protein, human; C579165:Chrna7 protein, rat; D051638:Ether-A-Go-Go Potassium Channels; C513163:N-(1-azabicyclo(2.2.2)oct-3-yl)furo(2,3-c)pyridine-5-carboxamide; D018722:Nicotinic Agonists; D018697:Nootropic Agents; D011812:Quinuclidines; D011978:Receptors, Nicotinic; D064569:alpha7 Nicotinic Acetylcholine Receptor