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

• Published in: European journal of medicinal chemistry 2019-10, Vol.179, p.608-622
• Main Authors: Li, Zheng, Liu, Chunxia, Yang, Jianyong, Zhou, Jiaqi, Ye, Zhiwen, Feng, Dazhi, Yue, Na, Tong, Jiayi, Huang, Wenlong, Qian, Hai
• Format: Article
• Language: English
• Subjects: Diabetes; FFA1; GPR40; Phenoxyacetic acid; Toxicity
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2019.06.087

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. Starting from previously abandoned phenoxyacetic acid moiety, we identified a superior agonist 14 (CPU014, EC50 = 15.7 nM) based on SAR study and toxicity screening. [Display omitted] •CPU014 was identified by comprehensive exploration of structure-activity relationship.•CPU014 revealed significantly reduced risk of hepatotoxicity compared to TAK-875.•CPU014 exhibited an excellent therapeutic window from 5 to 500 mg/kg.•CPU014 showed enhanced glucose-dependent insulin secretion.•CPU014 has good pharmacokinetic profiles.