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

  • Eur J Med Chem. 2019 Oct 1:179:608-622. doi: 10.1016/j.ejmech.2019.06.087.
Zheng Li  1 ,  Chunxia Liu  2 ,  Jianyong Yang  2 ,  Jiaqi Zhou  2 ,  Zhiwen Ye  2 ,  Dazhi Feng  2 ,  Na Yue  2 ,  Jiayi Tong  3 ,  Wenlong Huang  4 ,  Hai Qian  5
Affiliations
  • 1. Center of Drug Discovery, State Key Laboratory of Natural Medicines, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing, 210009, PR China; School of Pharmacy, Guangdong Pharmaceutical University, Guangzhou, 510006, PR China.
  • 2. Center of Drug Discovery, State Key Laboratory of Natural Medicines, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing, 210009, PR China.
  • 3. Zhongda Hospital, Southeast University, Nanjing, Jiangsu, 210009, China.
  • 4. Center of Drug Discovery, State Key Laboratory of Natural Medicines, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing, 210009, PR China; Jiangsu Key Laboratory of Drug Discovery for Metabolic Disease, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing, 210009, PR China. Electronic address: [email protected].
  • 5. Center of Drug Discovery, State Key Laboratory of Natural Medicines, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing, 210009, PR China; Jiangsu Key Laboratory of Drug Discovery for Metabolic Disease, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing, 210009, PR China. Electronic address: [email protected].
PMID: 31279294 DOI: 10.1016/j.ejmech.2019.06.087
Abstract

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.

Keywords
Diabetes; FFA1; GPR40; Phenoxyacetic acid; Toxicity.