Discovery and optimization of piperidyl benzamide derivatives as a novel class of 11beta-HSD1 inhibitors.
Discovery and optimization of a piperidyl benzamide series of 11beta-HSD1 inhibitors is described. This series was derived from a cyclohexyl benzamide lead structures to address PXR selectivity, high non-specific protein binding, poor solubility, limited in vivo exposure, and in vitro cytotoxicity issues observed with the cyclohexyl benzamide structures. These efforts led to the discovery of piperidyl benzamide 15 which features improved properties over the cyclohexyl benzamide derivatives.
Rew
Yosup
Y
Amgen Inc., 1120 Veterans Boulevard, South San Francisco, CA 94080, USA.
McMinn
Dustin L
DL
Wang
Zhulun
Z
He
Xiao
X
Hungate
Randall W
RW
Jaen
Juan C
JC
Sudom
Athena
A
Sun
Daqing
D
Tu
Hua
H
Ursu
Stefania
S
Villemure
Elisia
E
Walker
Nigel P C
NP
Yan
Xuelei
X
Ye
Qiuping
Q
Powers
Jay P
JP
D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1 / Q000037:antagonists & inhibitors* / Q000737:chemistry; D001549:Benzamides / Q000138:chemical synthesis* / Q000494:pharmacology; D018360:Crystallography, X-Ray / Q000379:methods; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy*; D015195:Drug Design; D022781:Hepatocytes / Q000187:drug effects; D006801:Humans; D020128:Inhibitory Concentration 50; D007328:Insulin / Q000378:metabolism*; D008861:Microsomes / Q000378:metabolism; D008956:Models, Chemical; D015394:Molecular Structure; D010880:Piperidines / Q000737:chemistry*; D012995:Solubility; D013329:Structure-Activity Relationship
D001549:Benzamides; D007328:Insulin; D010880:Piperidines; C037689:benzamide; D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1