Novel series of substituted biphenylmethyl urea derivatives as MCH-R1 antagonists for the treatment of obesity.
We have designed and synthesized two novel series of MCH-R1 antagonists based on a substituted biphenylmethyl urea core. SAR was explored, suggesting that optimal binding with the receptor was achieved when the biphenylmethyl group and the linker were substituted on the same nitrogen of the urea moiety. Compound 1-(3'-cyano-4-biphenylmethyl)-3-(2-hydroxy-1,1-dimethylethyl)-1-{2-[1-(4-methylbenzyl)-4-piperidinyl]ethyl}urea 2t showed the best antagonist binding activity to the MCH-R1 with a 43 nM K(i).
Galiano
Silvia
S
Unidad en Investigación y Desarrollo de Medicamentos, Centro de Investigación en Farmacobiología Aplicada, University of Navarra, c/Irunlarrea s/n, 31080 Pamplona, Spain.
Ceras
Javier
J
Cirauqui
Nuria
N
Pérez
Silvia
S
Juanenea
Laura
L
Rivera
Gildardo
G
Aldana
Ignacio
I
Monge
Antonio
A
D000818:Animals; D019440:Anti-Obesity Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D001713:Biphenyl Compounds / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D015195:Drug Design; D006801:Humans; D010880:Piperidines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D017481:Receptors, Somatostatin / Q000037:antagonists & inhibitors*; D014508:Urea / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology
C521399:1-(3'-cyano-4-biphenylmethyl)-3-(2-hydroxy-1,1-dimethylethyl)-1-(2-(1-(4-methylbenzyl)-4-piperidinyl)ethyl)urea; D019440:Anti-Obesity Agents; D001713:Biphenyl Compounds; C103263:MCHR1 protein, human; D010880:Piperidines; D017481:Receptors, Somatostatin; D014508:Urea