Bicyclo[2.2.2]octyltriazole inhibitors of 11β-hydoxysteroid dehydrogenase type 1. Pharmacological agents for the treatment of metabolic syndrome

Milana Maletic; Aaron Leeman; Michael Szymonifka; Steven S Mundt; Hratch J Zokian; Kashmira Shah; Jasminka Dragovic; Kathy Lyons; Rolf Thieringer; Anne H Vosatka; James Balkovec; Sherman T Waddell

doi:10.1016/j.bmcl.2011.01.018

Bicyclo[2.2.2]octyltriazole inhibitors of 11β-hydoxysteroid dehydrogenase type 1. Pharmacological agents for the treatment of metabolic syndrome

Bioorg Med Chem Lett. 2011 Apr 15;21(8):2568-72. doi: 10.1016/j.bmcl.2011.01.018. Epub 2011 Jan 11.

Authors

Milana Maletic¹, Aaron Leeman, Michael Szymonifka, Steven S Mundt, Hratch J Zokian, Kashmira Shah, Jasminka Dragovic, Kathy Lyons, Rolf Thieringer, Anne H Vosatka, James Balkovec, Sherman T Waddell

Affiliation

¹ Department of Medicinal Chemistry, Merck Research Laboratories, Rahway, NJ 07065, USA. [email protected]

PMID: 21421311
DOI: 10.1016/j.bmcl.2011.01.018

Abstract

Following the discovery of a metabolic 'soft-spot' on a bicyclo[2.2.2]octyltriazole lead, an extensive effort was undertaken to block the oxidative metabolism and improve PK of this potent HSD1 lead. In this communication, SAR survey focusing on various alkyl chain replacements will be detailed. This effort culminated in the discovery of a potent ethyl sulfone inhibitor with an improved PK profile across species and improved physical properties.

MeSH terms

11-beta-Hydroxysteroid Dehydrogenase Type 1 / antagonists & inhibitors*
11-beta-Hydroxysteroid Dehydrogenase Type 1 / metabolism
11-beta-Hydroxysteroid Dehydrogenase Type 2 / antagonists & inhibitors
11-beta-Hydroxysteroid Dehydrogenase Type 2 / metabolism
Animals
Bridged Bicyclo Compounds / chemistry*
Enzyme Inhibitors / chemistry*
Enzyme Inhibitors / pharmacokinetics
Enzyme Inhibitors / therapeutic use
Humans
Metabolic Syndrome / drug therapy*
Mice
Structure-Activity Relationship
Triazoles / chemistry*
Triazoles / pharmacokinetics
Triazoles / therapeutic use

Substances

Bridged Bicyclo Compounds
Enzyme Inhibitors
Triazoles
11-beta-Hydroxysteroid Dehydrogenase Type 1
11-beta-Hydroxysteroid Dehydrogenase Type 2