Design, synthesis and biological evaluation of novel FFA1/GPR40 agonists: New breakthrough in an old scaffold

• DOI: 10.1016/j.ejmech.2019.06.087
• Publication Date: 2019-07-01T01:37:13Z
• Authors: Zheng Li; Chunxia Liu; Jianyong Yang; Jiaqi Zhou; Zhiwen Ye; Dazhi Feng; Na Yue; Jiayi Tong; Wenlong Huang; Hai Qian
• Keywords: Male; 0301 basic medicine; Mice, Inbred ICR; Dose-Response Relationship, Drug; Molecular Structure; Acetates; Glucose Tolerance Test; Rats; Receptors, G-Protein-Coupled; 3. Good health; Mice, Inbred C57BL; Rats, Sprague-Dawley; Mice; Structure-Activity Relationship; 03 medical and health sciences; Diabetes Mellitus, Type 2; Drug Design; Animals; Hypoglycemic Agents

Based on an old phenoxyacetic acid scaffold, CPU014 (compound 14) has been identified as a superior agonist by comprehensive exploration of structure-activity relationship. In vitro toxicity study suggested that CPU014 has lower risk of hepatotoxicity than TAK-875. During acute toxicity study (5-500 mg/kg), a favorable therapeutic window of CPU014 was observed by evaluation of plasma profiles and liver slices. Moreover, CPU014 promotes insulin secretion in a glucose-dependent manner, while no GLP-1 secretion has been enhanced. Other than good pharmacokinetic properties, CPU014 significantly improved glucose tolerance both in normal and diabetic models without the risk of hypoglycemia. These subversive findings provided a safer candidate CPU014, which is currently in preclinical study to assess its potential for the treatment of diabetes.