title: Structure-based design and synthesis of 1,3-oxazinan-2-one inhibitors of 11β-hydroxysteroid dehydrogenase type 1.
abstract: Structure based design led directly to 1,3-oxazinan-2-one 9a with an IC(50) of 42 nM against 11β-HSD1 in vitro. Optimization of 9a for improved in vitro enzymatic and cellular potency afforded 25f with IC(50) values of 0.8 nM for the enzyme and 2.5 nM in adipocytes. In addition, 25f has 94% oral bioavailability in rat and >1000× selectivity over 11β-HSD2. In mice, 25f was distributed to the target tissues, liver, and adipose, and in cynomolgus monkeys a 10 mg/kg oral dose reduced cortisol production by 85% following a cortisone challenge.
authors.affiliation: Vitae Pharmaceuticals, 502 West Office Center Drive, Fort Washington, Pennsylvania 19034, USA.
authors.forename: Zhenrong
authors.initials: Z
authors.lastname: Xu
authors.forename: Colin M
authors.initials: CM
authors.lastname: Tice
authors.forename: Wei
authors.initials: W
authors.lastname: Zhao
authors.forename: Salvacion
authors.initials: S
authors.lastname: Cacatian
authors.forename: Yuan-Jie
authors.initials: YJ
authors.lastname: Ye
authors.forename: Suresh B
authors.initials: SB
authors.lastname: Singh
authors.forename: Peter
authors.initials: P
authors.lastname: Lindblom
authors.forename: Brian M
authors.initials: BM
authors.lastname: McKeever
authors.forename: Paula M
authors.initials: PM
authors.lastname: Krosky
authors.forename: Barbara A
authors.initials: BA
authors.lastname: Kruk
authors.forename: Jennifer
authors.initials: J
authors.lastname: Berbaum
authors.forename: Richard K
authors.initials: RK
authors.lastname: Harrison
authors.forename: Judith A
authors.initials: JA
authors.lastname: Johnson
authors.forename: Yuri
authors.initials: Y
authors.lastname: Bukhtiyarov
authors.forename: Reshma
authors.initials: R
authors.lastname: Panemangalore
authors.forename: Boyd B
authors.initials: BB
authors.lastname: Scott
authors.forename: Yi
authors.initials: Y
authors.lastname: Zhao
authors.forename: Joseph G
authors.initials: JG
authors.lastname: Bruno
authors.forename: Jennifer
authors.initials: J
authors.lastname: Togias
authors.forename: Joan
authors.initials: J
authors.lastname: Guo
authors.forename: Rong
authors.initials: R
authors.lastname: Guo
authors.forename: Patrick J
authors.initials: PJ
authors.lastname: Carroll
authors.forename: Gerard M
authors.initials: GM
authors.lastname: McGeehan
authors.forename: Linghang
authors.initials: L
authors.lastname: Zhuang
authors.forename: Wei
authors.initials: W
authors.lastname: He
authors.forename: David A
authors.initials: DA
authors.lastname: Claremon
mesh_terms: D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1 / Q000037:antagonists & inhibitors*; D017667:Adipocytes / Q000166:cytology / Q000187:drug effects* / Q000201:enzymology; D000284:Administration, Oral; D000818:Animals; D016466:CHO Cells; D002478:Cells, Cultured; D003348:Cortisone / Q000494:pharmacology; D006224:Cricetinae; D003412:Cricetulus; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology*; D006801:Humans; D008252:Macaca fascicularis; D051379:Mice; D010078:Oxazines / Q000737:chemistry*; D051381:Rats; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D013329:Structure-Activity Relationship; D014018:Tissue Distribution
chemical_list: D004791:Enzyme Inhibitors; D010078:Oxazines; D011994:Recombinant Proteins; D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1; D003348:Cortisone