Spirocyclic ureas: orally bioavailable 11 beta-HSD1 inhibitors identified by computer-aided drug design.
Structure-guided drug design led to the identification of a class of spirocyclic ureas which potently inhibit human 11beta-HSD1 in vitro. Lead compound 10j was shown to be orally bioavailable in three species, distributed into adipose tissue in the mouse, and its (R) isomer 10j2 was efficacious in a primate pharmacodynamic model.
Tice
Colin M
CM
Vitae Pharmaceuticals, 502 West Office Center Drive, Fort Washington, PA 19034, USA.
Zhao
Wei
W
Xu
Zhenrong
Z
Cacatian
Salvacion T
ST
Simpson
Robert D
RD
Ye
Yuan-Jie
YJ
Singh
Suresh B
SB
McKeever
Brian M
BM
Lindblom
Peter
P
Guo
Joan
J
Krosky
Paula M
PM
Kruk
Barbara A
BA
Berbaum
Jennifer
J
Harrison
Richard K
RK
Johnson
Judith J
JJ
Bukhtiyarov
Yuri
Y
Panemangalore
Reshma
R
Scott
Boyd B
BB
Zhao
Yi
Y
Bruno
Joseph G
JG
Zhuang
Linghang
L
McGeehan
Gerard M
GM
He
Wei
W
Claremon
David A
DA
D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000284:Administration, Oral; D000818:Animals; D001665:Binding Sites / Q000502:physiology; D001682:Biological Availability; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D015195:Drug Design; D006801:Humans; D008252:Macaca fascicularis; D051379:Mice; D051381:Rats; D013329:Structure-Activity Relationship; D014508:Urea / Q000008:administration & dosage* / Q000031:analogs & derivatives / Q000493:pharmacokinetics*
D014508:Urea; D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1