Selective Fyn kinase inhibitors for treatment of metabolic disease

描述（由申请人提供）：代谢性疾病，如2型糖尿病（T2D）、肥胖及其相关合并症已在全球范围内达到流行程度。虽然肥胖症和T2D的分子机制研究不断取得进展，但安全、有效的治疗方式的确定和发展仍显着有限。现在迫切需要创新药物来对抗肥胖和糖尿病。最近的数据以及我们的1期数据强烈表明，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途径。我们已经确定了一种有前途的选择性Fyn激酶抑制剂，并完成了初始合成反应，以产生一种新的选择性先导化合物。本提案描述了通过药物化学，体外表征和功能细胞活性进一步开发和优化我们的先导化合物的综合方法。通过优化模式推进的最有效的化合物将用于在2型糖尿病动物模型中验证该方法。

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.