title: Discovery of pyrazine carboxamide CB1 antagonists: the introduction of a hydroxyl group improves the pharmaceutical properties and in vivo efficacy of the series.
abstract: Structure-activity relationships for a series of pyrazine carboxamide CB1 antagonists are reported. Pharmaceutical properties of the series are improved via inclusion of hydroxyl-containing sidechains. This structural modification sufficiently improved ADME properties of an orally inactive series such that food intake reduction was achieved in rat feeding models. Compound 35 elicits a 46% reduction in food intake in ad libidum fed rats 4-h post-dose.
authors.affiliation: Pharmaceutical Research Institute, Bristol Myers Squibb Co., PO Box 5400 Princeton, NJ 08543, USA. Bruce.Ellsworth@bms.com
authors.forename: Bruce A
authors.initials: BA
authors.lastname: Ellsworth
authors.forename: Ying
authors.initials: Y
authors.lastname: Wang
authors.forename: Yeheng
authors.initials: Y
authors.lastname: Zhu
authors.forename: Annapurna
authors.initials: A
authors.lastname: Pendri
authors.forename: Samuel W
authors.initials: SW
authors.lastname: Gerritz
authors.forename: Chongqing
authors.initials: C
authors.lastname: Sun
authors.forename: Kenneth E
authors.initials: KE
authors.lastname: Carlson
authors.forename: Liya
authors.initials: L
authors.lastname: Kang
authors.forename: Rose A
authors.initials: RA
authors.lastname: Baska
authors.forename: Yifan
authors.initials: Y
authors.lastname: Yang
authors.forename: Qi
authors.initials: Q
authors.lastname: Huang
authors.forename: Neil T
authors.initials: NT
authors.lastname: Burford
authors.forename: Mary Jane
authors.initials: MJ
authors.lastname: Cullen
authors.forename: Susan
authors.initials: S
authors.lastname: Johnghar
authors.forename: Kamelia
authors.initials: K
authors.lastname: Behnia
authors.forename: Mary Ann
authors.initials: MA
authors.lastname: Pelleymounter
authors.forename: William N
authors.initials: WN
authors.lastname: Washburn
authors.forename: William R
authors.initials: WR
authors.lastname: Ewing
mesh_terms: D000577:Amides / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D011718:Pyrazinamide / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D051381:Rats; D043884:Receptor, Cannabinoid, CB1 / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship
chemical_list: D000577:Amides; D043884:Receptor, Cannabinoid, CB1; D011718:Pyrazinamide; C005296:pyrazinoic acid