title: 6-(4-chlorophenyl)-3-substituted-thieno[3,2-d]pyrimidin-4(3H)-one-based melanin-concentrating hormone receptor 1 antagonist.
abstract: Genetic manipulation studies in mice at both the MCH receptor 1 (MCHR1) as well as the MCH peptide levels have implicated MCHR1 as a key player in energy homeostasis. The phenotype exhibited by these studies, that is, increased metabolic rate, resistance to high fat diet, and subsequent weight loss, has spurred considerable efforts to develop antagonists of MCHR1. In continuation of efforts directed toward this goal, the present work capitalizes on the putative binding mode of an MCH antagonist, resulting in the identification of several novel chemotypes that are potent and selective MCHR1 antagonists. In addition, the favorable pharmacokinetics of representative examples has allowed for the evaluation of an MCHR1 antagonist in a high fat diet-induced obese rodent model of obesity. The tolerability of the right-hand side of the template for diverse chemotypes accompanied by favorable effects on weight loss enhances the attractiveness of this template in the pursuit toward development of effective anti-obesity agents.
authors.affiliation: Department of Medicinal Chemistry, GlaxoSmithKline, Research Triangle Park, North Carolina 27709, USA. fxt66911@gsk.com
authors.forename: Francis X
authors.initials: FX
authors.lastname: Tavares
authors.forename: Kamal A
authors.initials: KA
authors.lastname: Al-Barazanji
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Bishop
authors.forename: Christy S
authors.initials: CS
authors.lastname: Britt
authors.forename: David L
authors.initials: DL
authors.lastname: Carlton
authors.forename: Joel P
authors.initials: JP
authors.lastname: Cooper
authors.forename: Paul L
authors.initials: PL
authors.lastname: Feldman
authors.forename: Dulce M
authors.initials: DM
authors.lastname: Garrido
authors.forename: Aaron S
authors.initials: AS
authors.lastname: Goetz
authors.forename: Mary K
authors.initials: MK
authors.lastname: Grizzle
authors.forename: Donald L
authors.initials: DL
authors.lastname: Hertzog
authors.forename: Diane M
authors.initials: DM
authors.lastname: Ignar
authors.forename: Daniel G
authors.initials: DG
authors.lastname: Lang
authors.forename: Maggie S
authors.initials: MS
authors.lastname: McIntyre
authors.forename: Ronda J
authors.initials: RJ
authors.lastname: Ott
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Peat
authors.forename: Hui-Qiang
authors.initials: HQ
authors.lastname: Zhou
mesh_terms: D000818:Animals; D019440:Anti-Obesity Agents / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D001665:Binding Sites; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D051379:Mice; D011743:Pyrimidines / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D051381:Rats; D017481:Receptors, Somatostatin / Q000037:antagonists & inhibitors* / Q000737:chemistry; D013329:Structure-Activity Relationship; D013876:Thiophenes / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology
chemical_list: D019440:Anti-Obesity Agents; C103263:MCHR1 protein, human; D011743:Pyrimidines; D017481:Receptors, Somatostatin; D013876:Thiophenes