Discovery of 4-heteroarylbicyclo[2.2.2]octyltriazoles as potent and selective inhibitors of 11beta-HSD1: novel therapeutic agents for the treatment of metabolic syndrome

Xin Gu; Jasminka Dragovic; Gloria C Koo; Sam L Koprak; Cheryl LeGrand; Steven S Mundt; Kashmira Shah; Marty S Springer; Eugene Y Tan; Rolf Thieringer; Anne Hermanowski-Vosatka; Hratch J Zokian; James M Balkovec; Sherman T Waddell

doi:10.1016/j.bmcl.2005.08.052

Discovery of 4-heteroarylbicyclo[2.2.2]octyltriazoles as potent and selective inhibitors of 11beta-HSD1: novel therapeutic agents for the treatment of metabolic syndrome

Bioorg Med Chem Lett. 2005 Dec 1;15(23):5266-9. doi: 10.1016/j.bmcl.2005.08.052. Epub 2005 Sep 26.

Authors

Xin Gu¹, Jasminka Dragovic, Gloria C Koo, Sam L Koprak, Cheryl LeGrand, Steven S Mundt, Kashmira Shah, Marty S Springer, Eugene Y Tan, Rolf Thieringer, Anne Hermanowski-Vosatka, Hratch J Zokian, James M Balkovec, Sherman T Waddell

Affiliation

¹ Department of Medicinal Chemistry, Merck & Co., Inc., PO Box 2000, Rahway, NJ 07065, USA. [email protected]

PMID: 16185866
DOI: 10.1016/j.bmcl.2005.08.052

Abstract

Replacement of the pentyl chain on our original bicyclo[2.2.2]octyltriazole leads 1 and 2 has led to the discovery that heteroaryl substituted bicyclo[2.2.2]octyltriazoles are potent and selective 11beta-hydroxysteroid dehydrogenase type I (11beta-HSD1) inhibitors with excellent pharmacokinetic profiles.

MeSH terms

11-beta-Hydroxysteroid Dehydrogenase Type 1 / antagonists & inhibitors*
Animals
Enzyme Inhibitors / chemical synthesis
Enzyme Inhibitors / chemistry
Enzyme Inhibitors / therapeutic use
Humans
Metabolic Syndrome / drug therapy*
Mice
Triazoles / chemical synthesis
Triazoles / chemistry*
Triazoles / therapeutic use*

Substances

Enzyme Inhibitors
Triazoles
11-beta-Hydroxysteroid Dehydrogenase Type 1