DISCOVERY OF NOVEL FRUCTOSE BISPHOSPHATASE INHIBITORS

本研究的目标是开发通过抑制果糖-1，6-二磷酸酶（FBPase）降低肝脏和肾脏葡萄糖生成的化合物，FBPase是导致葡萄糖生成的葡萄糖生成途径中的倒数第二个酶之一。此类化合物可用于治疗糖尿病，特别是II型糖尿病。提出了通过合成和高通量筛选专有小分子库来鉴定新型FBPase抑制剂的策略，并通过组合和药物化学的组合来优化这些药剂，所述组合和药物化学由酶：抑制剂复合物的晶体结构的分子建模和测定指导。初步的文库筛选工作已经发现了一系列可逆的非碳水化合物、非核苷的人FBPase抑制剂。我们建议进一步研究和优化这种新型FBPase抑制剂系列，并通过继续高通量筛选我们的文库，继续发现其他结构类型的抑制剂。拟议的商业应用：由于在美国和世界范围内有大量的人患有糖尿病，并且治疗选择相对较少（参见第13- 15页），因此对新的糖尿病治疗方法的需求很大，特别是在II型糖尿病的情况下。我们提出的研究有望通过抑制果糖-1，6-二磷酸酶来鉴定新型葡萄糖产生抑制剂，该抑制剂可用于治疗糖尿病。

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.