Novel non-steroidal inhibitors of human 11β-hydroxysteroid dehydrogenase type 1

11 beta-Hydroxysteroid dehydrogenase type 1 (11 beta-HSD1) regulates glucocorticoid action at the pre-receptor stage by converting cortisone to cortisol. I I P-HSD I is selectively expressed in many tissues including the liver and adipose tissue where metabolic events are important. Metabolic syndrome relates to a number of metabolic abnormalities and currently has a prevalence of >20% in adult Americans. I I P-HSD I inhibitors are being investigated by many major pharmaceutical companies for type 2 diabetes and other abnormalities associated with metabolic syndrome. In this area of intense interest a number of structural types of I I P-HSD I inhibitor have been identified. It is important to have an array of structural types as the physicochemical properties of the compounds will determine tissue distribution, HPA effects, and ultimately clinical utility. Here we report the discovery and synthesis of three structurally different series of novel 11 beta-HSD1 inhibitors that inhibit human 11 beta-HSD1 in the low micromolar range. Docking studieswith 1-3 into the crystal structure of human 11p-HSD1 reveal how the molecules may interact with the enzyme and cofactor and give further scope for structure based drug design in the optimisation of these series. (C) 2007 Elsevier Ltd. All rights reserved.