The long-term goal of this proposal is to develop a new class of pharmacological agents that aid in the management of different aspects of the metabolic syndrome by modulating the levels of cortisol. The compounds could also be of use in the management of Cushing's syndrome in a patient subpopulation. Our approach consists of the design of inhibitors for 11 beta-hydroxysteroid dehydrogenase- type 1 (11bHSD-1), an oxidoreductase that acts as a key regulator of glucocorticoid levels in cells within the liver and adipose tissue. Elevated expression of 11 beta- HSD-1 in these target tissues has been shown to be a contributing factor in obesity, insulin resistance, hyperglycemia and Type 2 diabetes. In both mouse and human studies, modulation of this enzyme by either genetic or chemical means suggest that it holds significant promise for treatment of metabolic disorders. The goal of this phase 1 work is to identify small molecule inhibitors as potential clinical candidates for different metabolic disorders and as biological probes to further study the effects of the pharmacological inhibition of this enzyme. The workplan is composed of four steps: 1) the structure guided design of latent inhibitors for this enzyme; 2) selection, synthesis and characterization potential inhibitors; 3) enzymological evaluation of the ligands; 4) design, synthesis and evaluation of compounds with increased selectivity. During the Phase 1 we plan to demonstrate that latent selective inhibitors can be designed for this enzyme. In the process we will generate a small library of compounds that can be used as probes to study the pharmacoly of this enzyme. The second phase of these studies will evaluate the compounds in ex-vivo and in-vivo studies, with the ultimate purpose of identifying candidates for drug development
