Synthesis and structure-activity relationships of biarylcarboxamide bis-aminopyrrolidine urea derived small-molecule antagonists of the melanin-concentrating hormone receptor-1 (MCH-R1).
A novel series of bis-aminopyrrolidine ureas containing either a 4-biphenylcarboxmide or 5-phenyl-2-thiophenecarboxamide group have been identified as potent and functional antagonists of the melanin-concentrating hormone receptor-1. Syntheses and SAR are described, which led to the discovery of compounds with high binding affinity (Ki = 1 nM) for the receptor. Preliminary in vitro metabolic stability data are also reported for key compounds.
Rowbottom
Martin W
MW
Department of Medicinal Chemistry, Neurocrine Biosciences Inc., 12790 El Camino Real, San Diego, CA 92130, USA. mrowbottom@neurocrine.com
Vickers
Troy D
TD
Dyck
Brian
B
Tamiya
Junko
J
Zhang
Mingzhu
M
Zhao
Liren
L
Grey
Jonathan
J
Provencal
David
D
Schwarz
David
D
Heise
Christopher E
CE
Mistry
Monica
M
Fisher
Andrew
A
Dong
Teresa
T
Hu
Tao
T
Saunders
John
J
Goodfellow
Val S
VS
D000577:Amides / Q000138:chemical synthesis / Q000494:pharmacology; D000818:Animals; D015195:Drug Design; D008968:Molecular Conformation; D008970:Molecular Weight; D011759:Pyrrolidines / Q000138:chemical synthesis / Q000494:pharmacology; D051381:Rats; D017481:Receptors, Somatostatin / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship; D014508:Urea / Q000031:analogs & derivatives / Q000138:chemical synthesis / Q000494:pharmacology
D000577:Amides; C491208:MCHR1 protein, rat; D011759:Pyrrolidines; D017481:Receptors, Somatostatin; D014508:Urea