Discovery of orally efficacious melanin-concentrating hormone receptor-1 antagonists as antiobesity agents. Synthesis, SAR, and biological evaluation of bicyclo[3.1.0]hexyl ureas.
Melanin-concentrating hormone (MCH) is a cyclic, nonadecapeptide expressed in the CNS of all vertebrates that regulates feeding behavior and energy homeostasis via interaction with the central melanocortin system. Regulation of this interaction results in modulation of food intake and body weight gain, demonstrating significant therapeutic potential for the treatment of obesity. The MCH-1 receptor (MCH-R1) has been identified as a key target in MCH regulation, as small molecule antagonists of MCH-R1 have demonstrated activity in vivo. Herein, we document our research in a bicyclo[3.1.0]hexyl urea series with particular emphasis on structure-activity relationships and optimization of receptor occupancy, measured both in vitro and via an ex vivo binding assay following an oral dosing regimen. Several compounds have been tested in vivo and exhibit oral efficacy in relevant acute rodent feeding models. In particular, 24u has proven efficacious in chronic rodent models of obesity, showing a statistically significant reduction in food intake and body weight over a 28 day study.
Department of Chemical Research and Department of Cardiovascular and Metabolic Diseases, Schering-Plough Research Institute, 2015 Galloping Hill Road, Kenilworth, New Jersey 07033-0539, USA. mark.mcbriar@spcorp.com
Mark D
MD
McBriar
Henry
H
Guzik
Sherry
S
Shapiro
Jaroslava
J
Paruchova
Ruo
R
Xu
Anandan
A
Palani
John W
JW
Clader
Kathleen
K
Cox
William J
WJ
Greenlee
Brian E
BE
Hawes
Timothy J
TJ
Kowalski
Kim
K
O'neill
Brian D
BD
Spar
Blair
B
Weig
Daniel J
DJ
Weston
Constance
C
Farley
John
J
Cook
D000284:Administration, Oral; D000818:Animals; D019440:Anti-Obesity Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D001682:Biological Availability; D001835:Body Weight / Q000187:drug effects; D001921:Brain / Q000378:metabolism; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D004435:Eating / Q000187:drug effects; D006207:Half-Life; D008297:Male; D009765:Obesity / Q000188:drug therapy; D010671:Phenylurea Compounds / Q000138:chemical synthesis* / Q000494:pharmacology; D010879:Piperazines / Q000138:chemical synthesis* / Q000494:pharmacology; D011869:Radioligand Assay; D051381:Rats; D017481:Receptors, Somatostatin / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013329:Structure-Activity Relationship; D014018:Tissue Distribution; D014508:Urea / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000494:pharmacology
D019440:Anti-Obesity Agents; C103263:MCHR1 protein, human; C509929:N-(5-(4-cyanophenyl)bicyclo(3.1.0)hex-2-yl)-N'-(4-fluoro-3-(trifluoromethyl)phenyl)-N-(3-(4-methyl-1-piperazinyl)propyl)urea; D010671:Phenylurea Compounds; D010879:Piperazines; D017481:Receptors, Somatostatin; D014508:Urea