title: Optimization of novel di-substituted cyclohexylbenzamide derivatives as potent 11 beta-HSD1 inhibitors.
abstract: Novel 4,4-disubstituted cyclohexylbenzamide inhibitors of 11beta-HSD1 were optimized to account for liabilities relating to in vitro pharmacokinetics, cytotoxicity and protein-related shifts in potency. A representative compound showing favorable in vivo pharmacokinetics was found to be an efficacious inhibitor of 11beta-HSD1 in a rat pharmacodynamic model (ED(50)=10mg/kg).
authors.affiliation: Amgen, Inc., 1120 Veterans Boulevard, South San Francisco, CA 94080, USA.
authors.forename: Dustin L
authors.initials: DL
authors.lastname: McMinn
authors.forename: Yosup
authors.initials: Y
authors.lastname: Rew
authors.forename: Athena
authors.initials: A
authors.lastname: Sudom
authors.forename: Seb
authors.initials: S
authors.lastname: Caille
authors.forename: Michael
authors.initials: M
authors.lastname: Degraffenreid
authors.forename: Xiao
authors.initials: X
authors.lastname: He
authors.forename: Randall
authors.initials: R
authors.lastname: Hungate
authors.forename: Ben
authors.initials: B
authors.lastname: Jiang
authors.forename: Juan
authors.initials: J
authors.lastname: Jaen
authors.forename: Lisa D
authors.initials: LD
authors.lastname: Julian
authors.forename: Jacob
authors.initials: J
authors.lastname: Kaizerman
authors.forename: Perry
authors.initials: P
authors.lastname: Novak
authors.forename: Daqing
authors.initials: D
authors.lastname: Sun
authors.forename: Hua
authors.initials: H
authors.lastname: Tu
authors.forename: Stefania
authors.initials: S
authors.lastname: Ursu
authors.forename: Nigel P C
authors.initials: NP
authors.lastname: Walker
authors.forename: Xuelei
authors.initials: X
authors.lastname: Yan
authors.forename: Qiuping
authors.initials: Q
authors.lastname: Ye
authors.forename: Zhulun
authors.initials: Z
authors.lastname: Wang
authors.forename: Jay P
authors.initials: JP
authors.lastname: Powers
mesh_terms: D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000818:Animals; D001549:Benzamides / Q000737:chemistry* / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D006367:HeLa Cells; D006801:Humans; D008252:Macaca fascicularis; D051381:Rats; D017207:Rats, Sprague-Dawley; D013329:Structure-Activity Relationship
chemical_list: D001549:Benzamides; D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1