Selective Fyn kinase inhibitors for treatment of metabolic disease

描述(申请人提供)：代谢性疾病，如2型糖尿病(T2D)，肥胖及其相关的共病在世界范围内已经达到流行的程度。虽然在肥胖症和T2D的分子机制方面继续取得进展，但安全、有效的治疗方法的识别和开发仍然非常有限。迫切需要创新的药物来对抗肥胖症和糖尿病。最近的数据和我们的第一阶段数据有力地表明，Fyn激酶的药理干预为发现治疗代谢性疾病的新药提供了一个极好的靶点和新的方法。我们已经确定了一种有前景的选择性Fyn激酶抑制剂，并完成了初步的合成，以生成一种新的、选择性的先导化合物。这项建议描述了一种综合的方法，通过药物化学、体外鉴定和基于功能细胞的活性进一步开发和优化我们的先导化合物。经过优化范例的最有效化合物将被用于在2型糖尿病动物模型中验证这一方法。

DESCRIPTION (provided by applicant): Metabolic diseases such as type 2 diabetes (T2D), obesity and their related co-morbidities have reached epidemic proportions worldwide. While progress continues to be made into the molecular mechanisms involved in both obesity and T2D, the identification and development of safe, efficacious therapeutic modalities is significantly limited. There is an urgent need for innovative medicines to combat both obesity and diabetes. Recent data along with our Phase 1 data strongly suggest that pharmacological intervention of Fyn kinase provides an excellent target and novel approach for the discovery of new drugs to treat metabolic disease. We have identified a promising selective Fyn kinase inhibitor and completed initial SAR to generate a novel and selective lead compound. This proposal describes an integrated approach for further development and optimization of our lead compound through medicinal chemistry, in vitro characterization and functional cell-based activity. The most effective compounds advancing through the optimization paradigm will be used to validate this approach in animal models of type 2 diabetes.