Synthesis and evaluation of azabicyclo[3.2.1]octane derivatives as potent mixed vasopressin antagonists.
A series of biaryl amides containing an azabicyclooctane amine headpiece were synthesized and evaluated as mixed arginine vasopressin (AVP) receptor antagonists. Several analogues, including 8g, 12g, 13d, and 13g, were shown to have excellent V(1a)- and good V(2)-receptor binding affinities. Compound 13d was further profiled for drug-like properties and for an in vitro comparison with conivaptan, the program's mixed V(1a)/V(2)-receptor antagonist standard.
Crombie
Aimee L
AL
Chemical Sciences, Pfizer Global Research and Development, Collegeville, PA 19335, USA. aimeecrombie@hotmail.com
Antrilli
Thomas M
TM
Campbell
Brandon A
BA
Crandall
David L
DL
Failli
Amedeo A
AA
He
Yanan
Y
Kern
Jeffrey C
JC
Moore
William J
WJ
Nogle
Lisa M
LM
Trybulski
Eugene J
EJ
D000818:Animals; D065092:Antidiuretic Hormone Receptor Antagonists; D001127:Arginine Vasopressin / Q000037:antagonists & inhibitors*; D001372:Aza Compounds / Q000138:chemical synthesis* / Q000494:pharmacology; D001552:Benzazepines; D001643:Bridged Bicyclo Compounds / Q000138:chemical synthesis* / Q000494:pharmacology; D006801:Humans; D015394:Molecular Structure; D009795:Octanes / Q000138:chemical synthesis* / Q000494:pharmacology; D013329:Structure-Activity Relationship
D065092:Antidiuretic Hormone Receptor Antagonists; D001372:Aza Compounds; D001552:Benzazepines; D001643:Bridged Bicyclo Compounds; D009795:Octanes; C106389:conivaptan; D001127:Arginine Vasopressin