FBPase inhibitors for glycemic control in diabetes

描述（由申请人提供）：本研究的目标是优化 Ontogen的独特的、新颖的 果糖1，6-二磷酸酶（FBPase）的小分子抑制剂 调节糖尿病患者的葡萄糖水平。以前发现的线索将被 针对药物样性质、安全性、功效和口服生物利用度进行了优化。 这种成功的化合物最终将作为一种新型药物进入临床开发。 2型糖尿病的治疗血糖升高是导致糖尿病的主要原因。 糖尿病并发症。葡萄糖生产中的关键酶FBPase 是一个重要的治疗靶点。有力， 非碳水化合物，非核苷FBPase抑制剂（IC 50 < 10 μ M）， 通过Ontogen的组合文库的高通量筛选鉴定。 共沉淀研究表明，抑制剂结合一个新的网站在 FBPase同源四聚体的界面，防止环重组 对酶活性至关重要。高分辨率结构信息和 实验/计算的物理化学参数将指导优化。 使用专有OntoBLOCK（TM）合成的聚焦组合文库 使用Ontogen最先进的OntoCHROM（TM）进行纯化 系统，将针对FBPase进行筛选。基于细胞的分析将证实， 化合物抑制异生。渗透性的体外预测因子， 生物利用度和稳定性将优先考虑用于体内测试的化合物。 最后，临床前毒理学、代谢和药代动力学将确定 临床试验的发展候选人。 拟定商业应用： 由于美国和世界范围内患有糖尿病的人数不断增加， 和相对缺乏的治疗选择（见研究计划，“意义”），需要 新的糖尿病治疗方法至关重要，特别是对于2型糖尿病。 我们的研究 我的建议将建立在我们早期的发现之上，并有望确定一种临床发展。 通过抑制果糖-1，6- 二磷酸酶 这将为治疗中的血糖维持提供一种新的方法 糖尿病

DESCRIPTION (provided by applicant): 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.