Synthesis and optimization of arylsulfonylpiperazines as a novel class of inhibitors of 11 beta-hydroxysteroid dehydrogenase type 1 (11 beta-HSD1)

Daqing Sun; Zhulun Wang; Mario Cardozo; Rebekah Choi; Michael Degraffenreid; Yongmei Di; Xiao He; Juan C Jaen; Marc Labelle; Jinsong Liu; Ji Ma; Shichang Miao; Athena Sudom; Liang Tang; Hua Tu; Stefania Ursu; Nigel Walker; Xuelei Yan; Qiuping Ye; Jay P Powers

doi:10.1016/j.bmcl.2008.12.114

Synthesis and optimization of arylsulfonylpiperazines as a novel class of inhibitors of 11 beta-hydroxysteroid dehydrogenase type 1 (11 beta-HSD1)

Bioorg Med Chem Lett. 2009 Mar 1;19(5):1522-7. doi: 10.1016/j.bmcl.2008.12.114. Epub 2009 Jan 9.

PMID: 19181519
DOI: 10.1016/j.bmcl.2008.12.114

Abstract

The synthesis and SAR of a series of arylsulfonylpiperazine inhibitors of 11beta-HSD1 are described. Optimization rapidly led to potent, selective, and orally bioavailable inhibitors demonstrating efficacy in a cynomolgus monkey ex vivo enzyme inhibition model.

Publication types

Comparative Study

MeSH terms

11-beta-Hydroxysteroid Dehydrogenase Type 1 / antagonists & inhibitors*
11-beta-Hydroxysteroid Dehydrogenase Type 1 / metabolism
Administration, Oral
Animals
Arylsulfonic Acids / chemical synthesis*
Arylsulfonic Acids / classification
Arylsulfonic Acids / pharmacology
Biological Availability
Cell Line
Crystallography, X-Ray
Enzyme Stability / drug effects
Enzyme Stability / physiology
Humans
Macaca fascicularis
Mice
Piperazines / chemical synthesis*
Piperazines / classification
Piperazines / pharmacology
Rats
Structure-Activity Relationship

Substances

Arylsulfonic Acids
Piperazines
11-beta-Hydroxysteroid Dehydrogenase Type 1