Discovery and optimization of adamantyl carbamate inhibitors of 11β-HSD1

Colin M Tice; Wei Zhao; Paula M Krosky; Barbara A Kruk; Jennifer Berbaum; Judith A Johnson; Yuri Bukhtiyarov; Reshma Panemangalore; Boyd B Scott; Yi Zhao; Joseph G Bruno; Lamont Howard; Jennifer Togias; Yuan-Jie Ye; Suresh B Singh; Brian M McKeever; Peter R Lindblom; Joan Guo; Rong Guo; Herbert Nar; Annette Schuler-Metz; Richard E Gregg; Katerina Leftheris; Richard K Harrison; Gerard M McGeehan; Linghang Zhuang; David A Claremon

doi:10.1016/j.bmcl.2010.08.142

Discovery and optimization of adamantyl carbamate inhibitors of 11β-HSD1

Bioorg Med Chem Lett. 2010 Nov 15;20(22):6725-9. doi: 10.1016/j.bmcl.2010.08.142. Epub 2010 Sep 7.

Affiliation

¹ Vitae Pharmaceuticals, 502 W. Office Center Drive, Fort Washington, PA 19034, USA. [email protected]

PMID: 20864344
DOI: 10.1016/j.bmcl.2010.08.142

Abstract

Synthesis of 2-adamantyl carbamate derivatives of piperidines and pyrrolidines led to the discovery of 9a with an IC(50) of 15.2 nM against human 11β-HSD1 in adipocytes. Optimization for increased adipocyte potency, metabolic stability and selectivity afforded 11k and 11l, both of which were >25% orally bioavailable in rat.

MeSH terms

11-beta-Hydroxysteroid Dehydrogenase Type 1 / antagonists & inhibitors*
Adamantane / chemistry
Adamantane / pharmacology*
Animals
Drug Discovery
Enzyme Inhibitors / chemistry
Enzyme Inhibitors / pharmacology*
Models, Molecular
Rats

Substances

Enzyme Inhibitors
11-beta-Hydroxysteroid Dehydrogenase Type 1
Adamantane