Discovery and optimization of adamantyl carbamate inhibitors of 11β-HSD1.
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.
Tice
Colin M
CM
Vitae Pharmaceuticals, 502 W. Office Center Drive, Fort Washington, PA 19034, USA. ctice@vitaerx.com
Zhao
Wei
W
Krosky
Paula M
PM
Kruk
Barbara A
BA
Berbaum
Jennifer
J
Johnson
Judith A
JA
Bukhtiyarov
Yuri
Y
Panemangalore
Reshma
R
Scott
Boyd B
BB
Zhao
Yi
Y
Bruno
Joseph G
JG
Howard
Lamont
L
Togias
Jennifer
J
Ye
Yuan-Jie
YJ
Singh
Suresh B
SB
McKeever
Brian M
BM
Lindblom
Peter R
PR
Guo
Joan
J
Guo
Rong
R
Nar
Herbert
H
Schuler-Metz
Annette
A
Gregg
Richard E
RE
Leftheris
Katerina
K
Harrison
Richard K
RK
McGeehan
Gerard M
GM
Zhuang
Linghang
L
Claremon
David A
DA
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
D004791:Enzyme Inhibitors; D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1; D000218:Adamantane