FBPase inhibitors for glycemic control in diabetes

描述(申请人提供)：本研究的目标是优化 Ontogen的体外和体内特性在机制上独特，新颖， 小分子果糖1，6-二磷酸酶抑制剂(FBPase) 调节糖尿病患者的血糖水平。之前发现的线索将是 针对类药物特性、安全性、有效性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 糖尿病患者的并发症。葡萄糖生产中的关键酶--FBPase 通过糖异生，是一个重要的治疗靶点。强有力的， 非碳水化合物、非核苷类FBPase抑制剂(IC50‘S；10微米) 通过对Ontogen的组合文库的高通量筛选来鉴定。 共晶化研究表明，这些抑制剂在 FBPase同源四聚体的界面，防止环路重组 对酶活性至关重要。高分辨率构造信息和 实验/计算的物理化学参数将指导优化。 使用专有的OntoBLOCK(TM)合成的聚焦组合库 使用Ontogen最先进的OntoCHROM(TM)进行仪器和提纯 系统，将针对FBPase进行筛选。基于细胞的化验将证实 化合物抑制糖异生。通透性的体外预测指标， 生物利用度和稳定性将优先考虑化合物的体内测试。 最后，临床前毒理学、新陈代谢和药代动力学将确定 临床试验的开发候选者。 建议的商业应用： 由于美国和世界范围内患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 糖尿病的新治疗方法至关重要，尤其是对2型糖尿病。我们的研究 Proposal将建立在我们早期发现的基础上，并有望确定临床开发 将通过抑制果糖-1，6-减少过量葡萄糖产生的候选药物 双磷酸酶。这将为在治疗中维持血糖提供一种新的方法。 糖尿病的症状。

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.