title: Bicyclo[2.2.2]octyltriazole inhibitors of 11β-hydoxysteroid dehydrogenase type 1. Pharmacological agents for the treatment of metabolic syndrome.
abstract: Following the discovery of a metabolic 'soft-spot' on a bicyclo[2.2.2]octyltriazole lead, an extensive effort was undertaken to block the oxidative metabolism and improve PK of this potent HSD1 lead. In this communication, SAR survey focusing on various alkyl chain replacements will be detailed. This effort culminated in the discovery of a potent ethyl sulfone inhibitor with an improved PK profile across species and improved physical properties.
authors.affiliation: Department of Medicinal Chemistry, Merck Research Laboratories, Rahway, NJ 07065, USA. milana_maletic@merck.com
authors.forename: Milana
authors.initials: M
authors.lastname: Maletic
authors.forename: Aaron
authors.initials: A
authors.lastname: Leeman
authors.forename: Michael
authors.initials: M
authors.lastname: Szymonifka
authors.forename: Steven S
authors.initials: SS
authors.lastname: Mundt
authors.forename: Hratch J
authors.initials: HJ
authors.lastname: Zokian
authors.forename: Kashmira
authors.initials: K
authors.lastname: Shah
authors.forename: Jasminka
authors.initials: J
authors.lastname: Dragovic
authors.forename: Kathy
authors.initials: K
authors.lastname: Lyons
authors.forename: Rolf
authors.initials: R
authors.lastname: Thieringer
authors.forename: Anne H
authors.initials: AH
authors.lastname: Vosatka
authors.forename: James
authors.initials: J
authors.lastname: Balkovec
authors.forename: Sherman T
authors.initials: ST
authors.lastname: Waddell
mesh_terms: D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D043209:11-beta-Hydroxysteroid Dehydrogenase Type 2 / Q000037:antagonists & inhibitors / Q000378:metabolism; D000818:Animals; D001643:Bridged Bicyclo Compounds / Q000737:chemistry*; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000493:pharmacokinetics / Q000627:therapeutic use; D006801:Humans; D024821:Metabolic Syndrome / Q000188:drug therapy*; D051379:Mice; D013329:Structure-Activity Relationship; D014230:Triazoles / Q000737:chemistry* / Q000493:pharmacokinetics / Q000627:therapeutic use
chemical_list: D001643:Bridged Bicyclo Compounds; D004791:Enzyme Inhibitors; D014230:Triazoles; D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1; D043209:11-beta-Hydroxysteroid Dehydrogenase Type 2