Optimization of novel di-substituted cyclohexylbenzamide derivatives as potent 11 beta-HSD1 inhibitors.
Novel 4,4-disubstituted cyclohexylbenzamide inhibitors of 11beta-HSD1 were optimized to account for liabilities relating to in vitro pharmacokinetics, cytotoxicity and protein-related shifts in potency. A representative compound showing favorable in vivo pharmacokinetics was found to be an efficacious inhibitor of 11beta-HSD1 in a rat pharmacodynamic model (ED(50)=10mg/kg).
McMinn
Dustin L
DL
Amgen, Inc., 1120 Veterans Boulevard, South San Francisco, CA 94080, USA.
Rew
Yosup
Y
Sudom
Athena
A
Caille
Seb
S
Degraffenreid
Michael
M
He
Xiao
X
Hungate
Randall
R
Jiang
Ben
B
Jaen
Juan
J
Julian
Lisa D
LD
Kaizerman
Jacob
J
Novak
Perry
P
Sun
Daqing
D
Tu
Hua
H
Ursu
Stefania
S
Walker
Nigel P C
NP
Yan
Xuelei
X
Ye
Qiuping
Q
Wang
Zhulun
Z
Powers
Jay P
JP
D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000818:Animals; D001549:Benzamides / Q000737:chemistry* / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D006367:HeLa Cells; D006801:Humans; D008252:Macaca fascicularis; D051381:Rats; D017207:Rats, Sprague-Dawley; D013329:Structure-Activity Relationship
D001549:Benzamides; D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1