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

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.