title: Discovery and optimization of adamantyl carbamate inhibitors of 11β-HSD1.
abstract: Synthesis of 2-adamantyl carbamate derivatives of piperidines and pyrrolidines led to the discovery of 9a with an IC(50) of 15.2 nM against human 11β-HSD1 in adipocytes. Optimization for increased adipocyte potency, metabolic stability and selectivity afforded 11k and 11l, both of which were >25% orally bioavailable in rat.
authors.affiliation: Vitae Pharmaceuticals, 502 W. Office Center Drive, Fort Washington, PA 19034, USA. ctice@vitaerx.com
authors.forename: Colin M
authors.initials: CM
authors.lastname: Tice
authors.forename: Wei
authors.initials: W
authors.lastname: Zhao
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: 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: Lamont
authors.initials: L
authors.lastname: Howard
authors.forename: Jennifer
authors.initials: J
authors.lastname: Togias
authors.forename: Yuan-Jie
authors.initials: YJ
authors.lastname: Ye
authors.forename: Suresh B
authors.initials: SB
authors.lastname: Singh
authors.forename: Brian M
authors.initials: BM
authors.lastname: McKeever
authors.forename: Peter R
authors.initials: PR
authors.lastname: Lindblom
authors.forename: Joan
authors.initials: J
authors.lastname: Guo
authors.forename: Rong
authors.initials: R
authors.lastname: Guo
authors.forename: Herbert
authors.initials: H
authors.lastname: Nar
authors.forename: Annette
authors.initials: A
authors.lastname: Schuler-Metz
authors.forename: Richard E
authors.initials: RE
authors.lastname: Gregg
authors.forename: Katerina
authors.initials: K
authors.lastname: Leftheris
authors.forename: Richard K
authors.initials: RK
authors.lastname: Harrison
authors.forename: Gerard M
authors.initials: GM
authors.lastname: McGeehan
authors.forename: Linghang
authors.initials: L
authors.lastname: Zhuang
authors.forename: David A
authors.initials: DA
authors.lastname: Claremon
mesh_terms: D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1 / Q000037:antagonists & inhibitors*; D000218:Adamantane / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D055808:Drug Discovery; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D008958:Models, Molecular; D051381:Rats
chemical_list: D004791:Enzyme Inhibitors; D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1; D000218:Adamantane