Bioisosteric replacement of the hydrazide pharmacophore of the cannabinoid-1 receptor antagonist SR141716A. Part I: potent, orally-active 1,4-disubstituted imidazoles.
A new series of CB(1) receptor antagonists incorporating an imidazole-based isosteric replacement for the hydrazide moiety of rimonabant (SR141716) is disclosed. Members of this imidazole series possess potent/selective binding to the rCB(1) receptor and exhibit potent hCB(1) functional activity. Isopropyl analog 9a demonstrated activity in the tetrad assay and was orally-active in a food intake model.
Dow
Robert L
RL
Pfizer Global Research and Development, Groton, CT 06340, USA. robert.l.dow@pfizer.com
Hadcock
John R
JR
Scott
Dennis O
DO
Schneider
Steven R
SR
Paight
Ernest S
ES
Iredale
Philip A
PA
Carpino
Philip A
PA
Griffith
David A
DA
Hammond
Marlys
M
Dasilva-Jardine
Paul
P
D000818:Animals; D006801:Humans; D007093:Imidazoles / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D008958:Models, Molecular; D008968:Molecular Conformation; D010880:Piperidines / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D011720:Pyrazoles / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D051381:Rats; D043884:Receptor, Cannabinoid, CB1 / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D000077285:Rimonabant; D013329:Structure-Activity Relationship
D007093:Imidazoles; D010880:Piperidines; D011720:Pyrazoles; D043884:Receptor, Cannabinoid, CB1; D000077285:Rimonabant