Synthesis and optimization of novel 4,4-disubstituted cyclohexylbenzamide derivatives as potent 11β-HSD1 inhibitors

Daqing Sun; Zhulun Wang; Seb Caille; Michael DeGraffenreid; Felix Gonzalez-Lopez de Turiso; Randall Hungate; Juan C Jaen; Ben Jiang; Lisa D Julian; Ron Kelly; Dustin L McMinn; Jacob Kaizerman; Yosup Rew; Athena Sudom; Hua Tu; Stefania Ursu; Nigel Walker; Maren Willcockson; Xuelei Yan; Qiuping Ye; Jay P Powers

doi:10.1016/j.bmcl.2010.10.129

Synthesis and optimization of novel 4,4-disubstituted cyclohexylbenzamide derivatives as potent 11β-HSD1 inhibitors

Bioorg Med Chem Lett. 2011 Jan 1;21(1):405-10. doi: 10.1016/j.bmcl.2010.10.129. Epub 2010 Oct 31.

Affiliation

¹ Amgen Inc, 1120 Veterans Boulevard, South San Francisco, CA 94080, USA. [email protected]

PMID: 21093258
DOI: 10.1016/j.bmcl.2010.10.129

Abstract

The synthesis and SAR of a series of 4,4-disubstituted cyclohexylbenzamide inhibitors of 11β-HSD1 are described. Optimization rapidly led to potent, highly selective, and orally bioavailable inhibitors demonstrating efficacy in both rat and non-human primate ex vivo pharmacodynamic models.

MeSH terms

11-beta-Hydroxysteroid Dehydrogenase Type 1 / antagonists & inhibitors*
11-beta-Hydroxysteroid Dehydrogenase Type 1 / metabolism
Administration, Oral
Animals
Benzamides / chemical synthesis
Benzamides / chemistry*
Benzamides / pharmacokinetics
Binding Sites
Crystallography, X-Ray
Enzyme Inhibitors / chemical synthesis*
Enzyme Inhibitors / chemistry
Enzyme Inhibitors / pharmacokinetics
Humans
Macaca fascicularis
Microsomes, Liver / metabolism
Rats
Structure-Activity Relationship

Substances

Benzamides
Enzyme Inhibitors
11-beta-Hydroxysteroid Dehydrogenase Type 1