Azabicyclic sulfonamides as potent 11beta-HSD1 inhibitors

Unmesh Shah; Craig D Boyle; Samuel Chackalamannil; Hana Baker; Timothy Kowalski; Julie Lee; Giuseppe Terracina; Lili Zhang

doi:10.1016/j.bmcl.2010.01.082

Azabicyclic sulfonamides as potent 11beta-HSD1 inhibitors

Bioorg Med Chem Lett. 2010 Mar 1;20(5):1551-4. doi: 10.1016/j.bmcl.2010.01.082. Epub 2010 Jan 25.

Authors

Unmesh Shah¹, Craig D Boyle, Samuel Chackalamannil, Hana Baker, Timothy Kowalski, Julie Lee, Giuseppe Terracina, Lili Zhang

Affiliation

¹ Merck Research Laboratories, 2015 Galloping Hill Road, Kenilworth, NJ 07033, USA. unmesh.shah@spcorp.com

PMID: 20149650
DOI: 10.1016/j.bmcl.2010.01.082

Abstract

Inhibition of 11beta-HSD1 has demonstrated potential in the treatment of various components of metabolic syndrome. We wish to report herein the discovery of novel azabicyclic sulfonamide based 11beta-HSD1 inhibitors. Highly potent compounds exhibiting inhibitory activities at both human and mouse 11beta-HSD1 were identified. Several compounds demonstrated significant in vivo activity in the mouse cortisone challenge assay.

MeSH terms

11-beta-Hydroxysteroid Dehydrogenase Type 1 / antagonists & inhibitors*
11-beta-Hydroxysteroid Dehydrogenase Type 1 / metabolism
Animals
Azabicyclo Compounds / chemistry*
Cortisone / chemistry
Cortisone / metabolism
Enzyme Inhibitors / chemical synthesis
Enzyme Inhibitors / chemistry*
Enzyme Inhibitors / pharmacology
Humans
Hypoglycemic Agents / chemical synthesis
Hypoglycemic Agents / chemistry*
Hypoglycemic Agents / pharmacology
Mice
Structure-Activity Relationship
Sulfonamides / chemical synthesis
Sulfonamides / chemistry*
Sulfonamides / pharmacology

Substances

Azabicyclo Compounds
Enzyme Inhibitors
Hypoglycemic Agents
Sulfonamides
11-beta-Hydroxysteroid Dehydrogenase Type 1
Cortisone