title: Synthesis and structure-activity relationships of biarylcarboxamide bis-aminopyrrolidine urea derived small-molecule antagonists of the melanin-concentrating hormone receptor-1 (MCH-R1).
abstract: 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.
authors.affiliation: Department of Medicinal Chemistry, Neurocrine Biosciences Inc., 12790 El Camino Real, San Diego, CA 92130, USA. mrowbottom@neurocrine.com
authors.forename: Martin W
authors.initials: MW
authors.lastname: Rowbottom
authors.forename: Troy D
authors.initials: TD
authors.lastname: Vickers
authors.forename: Brian
authors.initials: B
authors.lastname: Dyck
authors.forename: Junko
authors.initials: J
authors.lastname: Tamiya
authors.forename: Mingzhu
authors.initials: M
authors.lastname: Zhang
authors.forename: Liren
authors.initials: L
authors.lastname: Zhao
authors.forename: Jonathan
authors.initials: J
authors.lastname: Grey
authors.forename: David
authors.initials: D
authors.lastname: Provencal
authors.forename: David
authors.initials: D
authors.lastname: Schwarz
authors.forename: Christopher E
authors.initials: CE
authors.lastname: Heise
authors.forename: Monica
authors.initials: M
authors.lastname: Mistry
authors.forename: Andrew
authors.initials: A
authors.lastname: Fisher
authors.forename: Teresa
authors.initials: T
authors.lastname: Dong
authors.forename: Tao
authors.initials: T
authors.lastname: Hu
authors.forename: John
authors.initials: J
authors.lastname: Saunders
authors.forename: Val S
authors.initials: VS
authors.lastname: Goodfellow
mesh_terms: 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
chemical_list: D000577:Amides; C491208:MCHR1 protein, rat; D011759:Pyrrolidines; D017481:Receptors, Somatostatin; D014508:Urea