title: SAR of biphenyl carboxamide ligands of the human melanin-concentrating hormone receptor 1 (MCH R1): discovery of antagonist SB-568849.
abstract: We report here the discovery of a class of MCH R1 ligands based on a biphenyl carboxamide template. A docked-in model is presented indicating key interactions in the putative binding site of the receptor. Parallel high throughput synthetic techniques were utilised to allow rapid exploration of the structure-activity relationship around this template, leading to compound SB-568849 which possessed good receptor affinity and selectivity. This compound proved to be an antagonist with stability in vivo, an acceptable brain-blood ratio and oral bioavailability.
authors.affiliation: GlaxoSmithKline, New Frontiers Science Park, Third Avenue, Harlow, Essex CM19 5AW, UK. david.witty@gsk.com
authors.forename: David R
authors.initials: DR
authors.lastname: Witty
authors.forename: John H
authors.initials: JH
authors.lastname: Bateson
authors.forename: Guillaume J
authors.initials: GJ
authors.lastname: Hervieu
authors.forename: Phillip
authors.initials: P
authors.lastname: Jeffrey
authors.forename: Christopher N
authors.initials: CN
authors.lastname: Johnson
authors.forename: Alison I
authors.initials: AI
authors.lastname: Muir
authors.forename: Peter J
authors.initials: PJ
authors.lastname: O'Hanlon
authors.forename: Geoffrey
authors.initials: G
authors.lastname: Stemp
authors.forename: Alex J
authors.initials: AJ
authors.lastname: Stevens
authors.forename: Kevin M
authors.initials: KM
authors.lastname: Thewlis
authors.forename: Shelagh
authors.initials: S
authors.lastname: Wilson
authors.forename: Kim Y
authors.initials: KY
authors.lastname: Winborn
mesh_terms: D000577:Amides / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D000818:Animals; D001713:Biphenyl Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D002417:Cattle; D019295:Computational Biology; D006801:Humans; D008024:Ligands; D008958:Models, Molecular; D015394:Molecular Structure; D017481:Receptors, Somatostatin / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D013329:Structure-Activity Relationship; D013455:Sulfur / Q000737:chemistry
chemical_list: D000577:Amides; D001713:Biphenyl Compounds; D008024:Ligands; C103263:MCHR1 protein, human; D017481:Receptors, Somatostatin; C514078:SB-568849; D013455:Sulfur