Biaryl ureas as potent and orally efficacious melanin concentrating hormone receptor 1 antagonists for the treatment of obesity.
Herein, we report a small molecule MCH-R1 antagonist which demonstrates oral efficacy in chronic rodent models. Substituted phenyl biaryl urea derivatives were synthesized and evaluated as MCH-R1 antagonists for the treatment of obesity. The structure-activity relationship studies in this series resulted in identification of urea 1 as a potent and selective MCH-R1 antagonist. Compound 1 exhibited oral efficacy in chronic (28 d) rodent models at 3-30 mpk showing significant reduction in food intake and weight gain relative to controls.
Palani
Anandan
A
Schering-Plough Research Institute, 2015 Galloping Hill Road, Kenilworth, New Jersey 07033, USA. anandan.palani@spcorp.com
Shapiro
Sherry
S
McBriar
Mark D
MD
Clader
John W
JW
Greenlee
William J
WJ
Spar
Brian
B
Kowalski
Timothy J
TJ
Farley
Constance
C
Cook
John
J
van Heek
Margaret
M
Weig
Blair
B
O'neill
Kim
K
Graziano
Michael
M
Hawes
Brian
B
D000284:Administration, Oral; D000818:Animals; D001835:Body Weight / Q000187:drug effects; D002118:Calcium / Q000378:metabolism; D002478:Cells, Cultured; D002908:Chronic Disease; D006801:Humans; D009765:Obesity / Q000188:drug therapy* / Q000378:metabolism; D051381:Rats; D017481:Receptors, Somatostatin / Q000037:antagonists & inhibitors* / Q000235:genetics; D013329:Structure-Activity Relationship; D014508:Urea / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000494:pharmacology
C103263:MCHR1 protein, human; C491208:MCHR1 protein, rat; D017481:Receptors, Somatostatin; D014508:Urea; D002118:Calcium