title: Substituted phenyl triazoles as selective inhibitors of 11β-Hydroxysteroid Dehydrogenase Type 1.
abstract: 3-(Phenylcyclobutyl)-1,2,4-triazoles were identified as inhibitors of 11β-Hydroxysteroid Dehydrogenase Type 1 (HSD1). They were shown to be active in the mouse in vivo pharmacodynamic model (PD) for HSD1 but exhibited a potent off-target activation of the Pregnane X Receptor (PXR). SAR studies and synthesis of analogs that led to the discovery of a selective HSD1 inhibitor are described in detail.
authors.affiliation: Department of Medicinal Chemistry, Merck & Co, Inc, PO Box 2000, Rahway, NJ 07065, USA. wanying_sun@merck.com
authors.forename: Wanying
authors.initials: W
authors.lastname: Sun
authors.forename: Milana
authors.initials: M
authors.lastname: Maletic
authors.forename: Steven S
authors.initials: SS
authors.lastname: Mundt
authors.forename: Kashmira
authors.initials: K
authors.lastname: Shah
authors.forename: Hratch
authors.initials: H
authors.lastname: Zokian
authors.forename: Kathy
authors.initials: K
authors.lastname: Lyons
authors.forename: Sherman T
authors.initials: ST
authors.lastname: Waddell
authors.forename: James
authors.initials: J
authors.lastname: Balkovec
mesh_terms: D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1 / Q000037:antagonists & inhibitors*; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D008958:Models, Molecular; D014230:Triazoles / Q000737:chemistry* / Q000494:pharmacology*
chemical_list: D004791:Enzyme Inhibitors; D014230:Triazoles; D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1