The long term goal of this proposal is the development a new class of pharmacological agents that modulate intraocular pressure by altering the levels of cortisol. Our approach consists of the design of inhibitors for an oxidoreductase that acts as a key regulator of glucocorticoid levels in cells and plays an important role in aqueous humor production. Non-selective inhibitors of this enzyme have shown in a clinical setting that they can indeed achieve such an effect. Unfortunately, no potent and selective inhibitors of the target enzyme that can be used in long term care are known. The goal of this phase 1 work is to identify such small molecule inhibitors as potential clinical candidates for the therapeutic management of glaucoma as well as further investigate the role of the target enzyme in the physiology of the eye. The workplan is composed of three steps: 1) the identification of inhibitors for this enzyme via compound acquisition and synthesis of potential inhibitors aided by structure guided methods; 2) enzymological evaluation of the ligands; 3) design, synthesis and evaluation of compounds with increased selectivity. During the Phase 1 we plan to demonstrate that selective inhibitors can be designed for this enzyme with the approach we are proposing. In the process we will generate a small library of compounds that can be used as probes to study the pharmacology 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
