title: Potent, selective, and orally efficacious antagonists of melanin-concentrating hormone receptor 1.
abstract: The high expression of MCH in the hypothalamus with the lean hypophagic phenotype coupled with increased resting metabolic rate and resistance to high fat diet-induced obesity of MCH KO mice has spurred considerable efforts to develop small molecule MCHR1 antagonists. Starting from a lead thienopyrimidinone series, structure-activity studies at the 3- and 6-positions of the thienopyrimidinone core afforded potent and selective MCHR1 antagonists with representative examples having suitable pharmacokinetic properties. Based on structure-activity relationships, a structural model for MCHR1 was constructed to explain the binding mode of these antagonists. In general, a good correlation was observed between pKas and activity in the right-hand side of the template, with Asp123 playing an important role in the enhancement of binding affinity. A representative example when evaluated chronically in diet-induced obese mice resulted in good weight loss effects. These antagonists provide a viable lead series in the discovery of new therapies for the treatment of obesity.
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: Eric C
authors.initials: EC
authors.lastname: Bigham
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: Paul L
authors.initials: PL
authors.lastname: Feldman
authors.forename: Aaron S
authors.initials: AS
authors.lastname: Goetz
authors.forename: Mary K
authors.initials: MK
authors.lastname: Grizzle
authors.forename: Yu C
authors.initials: YC
authors.lastname: Guo
authors.forename: Anthony L
authors.initials: AL
authors.lastname: Handlon
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: 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: D000284:Administration, Oral; D000818:Animals; D019440:Anti-Obesity Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001682:Biological Availability; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels / Q000187:drug effects / Q000502:physiology; D017930:Genes, Reporter; D006207:Half-Life; D006801:Humans; D051379:Mice; D008820:Mice, Obese; D008958:Models, Molecular; D011743:Pyrimidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D051381:Rats; D017481:Receptors, Somatostatin / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship; D013876:Thiophenes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
chemical_list: D019440:Anti-Obesity Agents; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; C103263:MCHR1 protein, human; D011743:Pyrimidines; D017481:Receptors, Somatostatin; D013876:Thiophenes