title: Discovery and optimization of piperidyl benzamide derivatives as a novel class of 11beta-HSD1 inhibitors.
abstract: Discovery and optimization of a piperidyl benzamide series of 11beta-HSD1 inhibitors is described. This series was derived from a cyclohexyl benzamide lead structures to address PXR selectivity, high non-specific protein binding, poor solubility, limited in vivo exposure, and in vitro cytotoxicity issues observed with the cyclohexyl benzamide structures. These efforts led to the discovery of piperidyl benzamide 15 which features improved properties over the cyclohexyl benzamide derivatives.
authors.affiliation: Amgen Inc., 1120 Veterans Boulevard, South San Francisco, CA 94080, USA.
authors.forename: Yosup
authors.initials: Y
authors.lastname: Rew
authors.forename: Dustin L
authors.initials: DL
authors.lastname: McMinn
authors.forename: Zhulun
authors.initials: Z
authors.lastname: Wang
authors.forename: Xiao
authors.initials: X
authors.lastname: He
authors.forename: Randall W
authors.initials: RW
authors.lastname: Hungate
authors.forename: Juan C
authors.initials: JC
authors.lastname: Jaen
authors.forename: Athena
authors.initials: A
authors.lastname: Sudom
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: Elisia
authors.initials: E
authors.lastname: Villemure
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: Jay P
authors.initials: JP
authors.lastname: Powers
mesh_terms: D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1 / Q000037:antagonists & inhibitors* / Q000737:chemistry; D001549:Benzamides / Q000138:chemical synthesis* / Q000494:pharmacology; D018360:Crystallography, X-Ray / Q000379:methods; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy*; D015195:Drug Design; D022781:Hepatocytes / Q000187:drug effects; D006801:Humans; D020128:Inhibitory Concentration 50; D007328:Insulin / Q000378:metabolism*; D008861:Microsomes / Q000378:metabolism; D008956:Models, Chemical; D015394:Molecular Structure; D010880:Piperidines / Q000737:chemistry*; D012995:Solubility; D013329:Structure-Activity Relationship
chemical_list: D001549:Benzamides; D007328:Insulin; D010880:Piperidines; C037689:benzamide; D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1