Selective Fyn kinase inhibitors for treatment of metabolic disease

用于治疗代谢疾病的选择性 Fyn 激酶抑制剂

基本信息

批准号：
8712859
负责人：
BENJAMIN M BUEHRER
金额：
$ 85.54万
依托单位：
ZEN-BIO, INC.
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-09-05 至 2016-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8712859
关键词：
Adipocytes Animal Model Biological Assay Biological Availability Biological Markers Biological Models Cell model Cells Characteristics Comorbidity Data Development Diabetes Mellitus Diet Dose Drug Kinetics Epidemic Fatty Acids Glucose Hepatocyte Histopathology Human In Vitro Intervention Lead MAPK14 gene Medicine Metabolic Metabolic Diseases Metabolism Metric Modality Modeling Modification Molecular Monitor Non-Insulin-Dependent Diabetes Mellitus Obesity Organ Pathway interactions Pharmaceutical Chemistry Pharmaceutical Preparations Phase Phosphotransferases Play Process Rodent Model Role Serum Skeletal Muscle Specificity Testing Therapeutic Toxic effect Validation analog base blood glucose regulation combat cross reactivity design enzyme substrate fatty acid metabolism glucose output glucose tolerance improved in vivo in vivo Model inhibitor/antagonist innovation insulin secretion insulin sensitivity islet kinase inhibitor lipid biosynthesis meetings next generation novel novel strategies phase 1 study public health relevance screening small molecule src-Family Kinases uptake

项目摘要

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.

描述（由申请人提供）：诸如2型糖尿病（T2D），肥胖及其相关的合并症等代谢疾病已在全球范围内达到流行病。尽管进展继续涉及肥胖和T2D涉及的分子机制，但安全，有效的治疗方式的识别和发展受到明显的限制。迫切需要创新的药物来对抗肥胖和糖尿病。最近的数据以及我们的1阶段数据强烈表明，FYN激酶的药理学干预为发现新药治疗代谢疾病提供了一种绝佳的靶标和新方法。我们已经确定了一种有希望的选择性FYN激酶抑制剂，并完成了初始SAR，以生成一种新颖的选择性铅化合物。该建议描述了通过药物化学，体外表征和基于功能细胞的活性进一步开发和优化铅化合物的综合方法。通过优化范式前进的最有效的化合物将用于在2型糖尿病的动物模型中验证这种方法。