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

Zheng Li; Chunxia Liu; Jianyong Yang; Jiaqi Zhou; Zhiwen Ye; Dazhi Feng; Na Yue; Jiayi Tong; Wenlong Huang; Hai Qian

doi:10.1016/j.ejmech.2019.06.087

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. Epub 2019 Jul 1.

Authors

Zheng Li¹, Chunxia Liu², Jianyong Yang², Jiaqi Zhou², Zhiwen Ye², Dazhi Feng², Na Yue², Jiayi Tong³, Wenlong Huang⁴, Hai Qian⁵

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: ydhuangwenlong@126.com.
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: qianhai24@163.com.

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.

MeSH terms

Acetates / chemical synthesis
Acetates / chemistry
Acetates / pharmacology*
Animals
Diabetes Mellitus, Type 2 / drug therapy*
Diabetes Mellitus, Type 2 / metabolism
Dose-Response Relationship, Drug
Drug Design*
Glucose Tolerance Test
Hypoglycemic Agents / chemical synthesis
Hypoglycemic Agents / chemistry
Hypoglycemic Agents / pharmacology*
Male
Mice
Mice, Inbred C57BL
Mice, Inbred ICR
Molecular Structure
Rats
Rats, Sprague-Dawley
Receptors, G-Protein-Coupled / agonists*
Receptors, G-Protein-Coupled / metabolism
Structure-Activity Relationship

Substances

Acetates
Ffar1 protein, mouse
G-protein-coupled receptor 40, rat
Hypoglycemic Agents
Receptors, G-Protein-Coupled
phenoxyacetic acid