DISCOVERY OF NOVEL FRUCTOSE BISPHOSPHATASE INHIBITORS

这项研究的目标是开发通过抑制果糖-1，6-二磷酸酶(FBPase)来降低肝脏和肾脏葡萄糖产生的化合物。果糖-1，6-二磷酸酶(FBPase)是导致葡萄糖产生的葡萄糖发生途径中倒数第二个酶之一。这些化合物在治疗糖尿病，特别是II型糖尿病方面将是有用的。提出了通过合成和高通量筛选专有小分子文库来鉴定新型FBPase抑制剂的策略，以及在分子模拟和确定酶：抑制剂复合体的晶体结构的指导下，通过组合化学和药物化学相结合来优化这些药物的策略。初步的文库筛选工作已经发现了一系列可逆的人类FBPase的非碳水化合物、非核苷抑制剂。我们建议进一步研究和优化这一新型FBPase抑制剂系列，并通过对我们的文库进行持续的高通量筛选，继续对其他结构类别的抑制剂进行发现。拟议的商业应用：由于美国和世界范围内患有糖尿病的人数众多，而治疗选择相对匮乏(见第13-15页)，因此对新的糖尿病疗法的需求很大，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-1，6-二磷酸酶来识别新的葡萄糖生成抑制剂，该酶可用于糖尿病的治疗。

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.