Design, synthesis, structure-activity relationship, and in vivo activity of azabicyclic aryl amides as alpha7 nicotinic acetylcholine receptor agonists.
A novel set of azabicyclic aryl amides have been identified as potent and selective agonists of the alpha7 nAChR. A two-pronged approach was taken to improve the potential hERG liability of previously disclosed alpha7 nAChR agonist, PNU-282,987, while maintaining the compound's other desirable pharmacological properties. The first approach involved further exploration of the aryl carboxylic acid fragment of PNU-282,987, while the second approach focused on modification of the azabicyclic amine portion of PNU-282,987. The best compounds from each series are characterized by rapid brain penetration, good oral bioavailability in rat, and demonstrate in vivo efficacy in a rat P50 auditory sensory gating assay. At least one analog from each series (1h, 1o, 2a, 9a, and 18a) shows an improved hERG safety profile over PNU-282,987.
Walker
Daniel P
DP
Neuroscience Research, Pfizer Global Research and Development, Eastern Point Rd., Groton, CT 06340, USA.
Wishka
Donn G
DG
Piotrowski
David W
DW
Jia
Shaojuan
S
Reitz
Steven C
SC
Yates
Karen M
KM
Myers
Jason K
JK
Vetman
Tatiana N
TN
Margolis
Brandon J
BJ
Jacobsen
E Jon
EJ
Acker
Brad A
BA
Groppi
Vincent E
VE
Wolfe
Mark L
ML
Thornburgh
Bruce A
BA
Tinholt
Paula M
PM
Cortes-Burgos
Luz A
LA
Walters
Rodney R
RR
Hester
Matthew R
MR
Seest
Eric P
EP
Dolak
Lester A
LA
Han
Fusen
F
Olson
Barbara A
BA
Fitzgerald
Laura
L
Staton
Brian A
BA
Raub
Thomas J
TJ
Hajos
Mihaly
M
Hoffmann
William E
WE
Li
Kai S
KS
Higdon
Nicole R
NR
Wall
Theron M
TM
Hurst
Raymond S
RS
Wong
Erik H F
EH
Rogers
Bruce N
BN
D000818:Animals; D001921:Brain / Q000378:metabolism*; D002038:Bungarotoxins; D002478:Cells, Cultured; D015195:Drug Design; D004594:Electrophysiology; D005072:Evoked Potentials, Auditory / Q000187:drug effects; D006624:Hippocampus / Q000187:drug effects; D015640:Ion Channel Gating / Q000187:drug effects; D015394:Molecular Structure; D009043:Motor Activity / Q000187:drug effects; D009474:Neurons / Q000187:drug effects; D018722:Nicotinic Agonists / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D018408:Patch-Clamp Techniques; D051381:Rats; D017207:Rats, Sprague-Dawley; D011978:Receptors, Nicotinic / Q000737:chemistry*; D013329:Structure-Activity Relationship; D013569:Synapses / Q000187:drug effects / Q000502:physiology; D064569:alpha7 Nicotinic Acetylcholine Receptor
D002038:Bungarotoxins; C579165:Chrna7 protein, rat; D018722:Nicotinic Agonists; D011978:Receptors, Nicotinic; D064569:alpha7 Nicotinic Acetylcholine Receptor