Discovery of novel, potent benzamide inhibitors of 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1) exhibiting oral activity in an enzyme inhibition ex vivo model.
We report the discovery of potent benzamide inhibitors of 11beta-hydroxysteroid dehydrogenase (11beta-HSD1). The optimization and correlation of in vitro and in vivo metabolic stability will be described. Through modifications to our initial lead 2, we discovered pyridyl compound 13. This compound has a favorable pharmacokinetic profile across three species and showed a dose-dependent decrease in adipose 11beta-HSD1 activity in a monkey ex vivo pharmacodynamic model.
Amgen, Inc., 1120 Veterans Boulevard, South San Francisco, California 94080, USA. ljulian@amgen.com
Lisa D
LD
Julian
Zhulun
Z
Wang
Tracy
T
Bostick
Seb
S
Caille
Rebekah
R
Choi
Michael
M
DeGraffenreid
Yongmei
Y
Di
Xiao
X
He
Randall W
RW
Hungate
Juan C
JC
Jaen
Jinsong
J
Liu
Mario
M
Monshouwer
Dustin
D
McMinn
Yosup
Y
Rew
Athena
A
Sudom
Daqing
D
Sun
Hua
H
Tu
Stefania
S
Ursu
Nigel
N
Walker
Xuelei
X
Yan
Qiuping
Q
Ye
Jay P
JP
Powers
D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1 / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D000284:Administration, Oral; D000818:Animals; D001549:Benzamides / Q000008:administration & dosage* / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism; D002460:Cell Line; D018360:Crystallography, X-Ray; D004285:Dogs; D004791:Enzyme Inhibitors / Q000008:administration & dosage* / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D008252:Macaca fascicularis; D023421:Models, Animal; D008958:Models, Molecular; D015394:Molecular Structure; D051381:Rats; D013329:Structure-Activity Relationship
D001549:Benzamides; D004791:Enzyme Inhibitors; C037689:benzamide; D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1