SBIR-STTR Award

The goal of this research is to develop compounds that lower hepatic and renal glucose production through the inhibition of fructose-1,6- bisphosphatase (FBPase), one of the penultimate enzymes in the gluconeogenesis pathway leading to the production of glucose. Such compounds would be useful in the treatment of diabetes, particularly Type II diabetes. Strategies are proposed for the identification of novel FBPase inhibitors through synthesis and high throughput screening of proprietary small molecule libraries, and optimization of these agents through a combination of combinatorial and medicinal chemistry guided by molecular modeling and determination of the crystal structures of enzyme:inhibitor complexes. Preliminary library screening efforts have uncovered a series of reversible non-carbohydrate, non-nucleoside inhibitors of human FBPase. We propose to further investigate and optimize this novel FBPase inhibitor series and to continue the discovery process towards other structural classes of inhibitors by continued high throughput screening of our libraries. PROPOSED COMMERCIAL APPLICATIONS: Because of the large number of people suffering from diabetes in the US and worldwide, and a relative paucity of treatment options (see pages 13- 15), the need for new diabetes therapeutics is large, particularly in the case of Type II diabetes. The research we propose is expected to lead to the identification of novel inhibitors of glucose production, through inhibition of fructose-1,6-bisphosphatase, which could be used in the treatment of diabetes.

The goal of this research is to optimize in vitro and in vivo properties of Ontogen's mechanistically unique, novel, small molecule inhibitors of fructose 1,6-bisphosphatase (FBPase) for use in regulating glucose levels in diabetics. Previously discovered leads will be optimized for drug-like properties, safety, efficacy, and oral bioavailability. The successful compound will ultimately enter clinical development as a novel treatment for type 2 diabetes. Elevated blood glucose is a major cause of complications in diabetics. FBPase, a key enzyme in the production of glucose via gluconeogenesis, represents an important therapeutic target. Potent, non-carbohydrate, non-nucleoside FBPase inhibitors (IC50's < 10 microM) were identified by high-throughput screening of Ontogen's combinatorial libraries. Cocrystallization studies revealed the inhibitors bind a novel site at the interface of the FBPase homotetramer, preventing reorganization of loops critical for enzymatic activity. High-resolution structural information and experimental/computed physicochemical parameters will guide optimization. Focused combinatorial libraries, synthesized using proprietary OntoBLOCK(TM) instrumentation and purified with Ontogen's state-of-the-art OntoCHROM(TM) system, will be screened against FBPase. Cell-based assays will confirm that compounds inhibit gluconeogenesis. In vitro predictors of permeability, bioavailability, and stability will prioritize compounds for in vivo testing. Finally, preclinical toxicology, metabolism and pharmacokinetics will identify a development candidate for clinical trials. PROPOSED COMMERCIAL APPLICATION: Because of the increasing number of people suffering from diabetes in the US and worldwide, and a relative paucity of treatment options (see Research Plan, "Significance"), the need for new treatments for diabetes is critical, particularly for type 2 diabetes. The research we propose will build on our earlier discoveries and is expected to identify a clinical development candidate that will reduce excess glucose production via inhibition of fructose-1,6- bisphosphatase. This will provide a novel approach for glucose maintenance in the treatment of diabetes