title: Synthesis of novel bicyclo[4.1.0]heptane and bicyclo[3.1.0]hexane derivatives as melanin-concentrating hormone receptor R1 antagonists.
abstract: To address the hERG liability of MCHR1 antagonists such as 1 and 2, new analogs such as 4 and 5 that incorporated a polar heteroaryl group were designed and synthesized. Biological evaluation confirmed that these new analogs retained MCH R1 activity with greatly attenuated hERG liabilities as indicated in the Rb efflux assay.
authors.affiliation: Department of Chemical Research, Schering-Plough Research Institute K15 2545, Kenilworth, NJ 07033, USA. jing.su@spcorp.com
authors.forename: Jing
authors.initials: J
authors.lastname: Su
authors.forename: Haiqun
authors.initials: H
authors.lastname: Tang
authors.forename: Brian A
authors.initials: BA
authors.lastname: McKittrick
authors.forename: Huizhong
authors.initials: H
authors.lastname: Gu
authors.forename: Tao
authors.initials: T
authors.lastname: Guo
authors.forename: Gang
authors.initials: G
authors.lastname: Qian
authors.forename: Duane A
authors.initials: DA
authors.lastname: Burnett
authors.forename: John W
authors.initials: JW
authors.lastname: Clader
authors.forename: William J
authors.initials: WJ
authors.lastname: Greenlee
authors.forename: Brian E
authors.initials: BE
authors.lastname: Hawes
authors.forename: Kim
authors.initials: K
authors.lastname: O'neill
authors.forename: Brian
authors.initials: B
authors.lastname: Spar
authors.forename: Blair
authors.initials: B
authors.lastname: Weig
authors.forename: Timothy
authors.initials: T
authors.lastname: Kowalski
authors.forename: Steve
authors.initials: S
authors.lastname: Sorota
mesh_terms: D000818:Animals; D002626:Chemistry, Pharmaceutical / Q000379:methods*; D015195:Drug Design; D004353:Drug Evaluation, Preclinical; D005399:Fishes; D006536:Heptanes / Q000737:chemistry*; D006586:Hexanes / Q000737:chemistry*; D006801:Humans; D007700:Kinetics; D051379:Mice; D008956:Models, Chemical; D015394:Molecular Structure; D009765:Obesity / Q000188:drug therapy; D017481:Receptors, Somatostatin / Q000037:antagonists & inhibitors*
chemical_list: D006536:Heptanes; D006586:Hexanes; C103263:MCHR1 protein, human; D017481:Receptors, Somatostatin