A potent free fatty acid receptor 1 agonist with a glucose-dependent antihyperglycemic effect

Xuekun Wang; Yurui Xu; Shujun Feng; Xinyu Huang; Xia Meng; Jiao Chen; Leilei Guo; Junliang Ge; Jikang Zhang; Jianmei Chen; Li Cheng; Kai Gu; Yu Zhang; Qing Jiang; Xinghai Ning

doi:10.1039/c9cc04040d

A potent free fatty acid receptor 1 agonist with a glucose-dependent antihyperglycemic effect

Chem Commun (Camb). 2019 Aug 7;55(61):8975-8978. doi: 10.1039/c9cc04040d. Epub 2019 Jul 10.

Authors

Xuekun Wang¹, Yurui Xu², Shujun Feng², Xinyu Huang², Xia Meng², Jiao Chen³, Leilei Guo², Junliang Ge², Jikang Zhang², Jianmei Chen², Li Cheng², Kai Gu⁴, Yu Zhang², Qing Jiang⁵, Xinghai Ning²

Affiliations

¹ Department of Biomedical Engineering, Nanjing National Laboratory of Microstructures, College of Engineering and Applied Sciences, Nanjing University, Nanjing 210093, P. R. China. zhangyu2007sm@163.com xning@nju.edu.cn and Department of Pharmaceutical Engineering, College of Pharmacy, Liaocheng University, Liaocheng 252059, P. R. China.
² Department of Biomedical Engineering, Nanjing National Laboratory of Microstructures, College of Engineering and Applied Sciences, Nanjing University, Nanjing 210093, P. R. China. zhangyu2007sm@163.com xning@nju.edu.cn.
³ Jiangsu Province Academy of Traditional Chinese Medicine, Nanjing 210028, P. R. China.
⁴ Department of Biomedical Engineering, Nanjing National Laboratory of Microstructures, College of Engineering and Applied Sciences, Nanjing University, Nanjing 210093, P. R. China. zhangyu2007sm@163.com xning@nju.edu.cn and Colleges of Medicine, State Key Laboratory of Natural Medicines, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, P. R. China.
⁵ The Center of Diagnosis and Treatment for Joint Disease, Drum Tower Hospital Affiliated with the Medical School of Nanjing University, Nanjing 210008, P. R. China. qingj@nju.edu.cn.

PMID: 31290492
DOI: 10.1039/c9cc04040d

Abstract

We present a novel free fatty acid receptor 1 (FFA1) agonist, named PAFA, with a strong agonist potency (EC₅₀ = 6.04 nM) and good serum stability. PAFA significantly stimulates insulin secretion in INS-1 cells in a glucose-dependent manner and exhibits high antihyperglycemic effects in db/db mice without adverse effects.

MeSH terms

Acetates / administration & dosage
Acetates / chemical synthesis
Acetates / therapeutic use*
Acetates / toxicity
Administration, Oral
Animals
Benzofurans / chemistry
Benzofurans / metabolism
Biphenyl Compounds / administration & dosage
Biphenyl Compounds / chemical synthesis
Biphenyl Compounds / therapeutic use*
Biphenyl Compounds / toxicity
CHO Cells
Cricetulus
Diabetes Mellitus, Experimental / drug therapy*
Dose-Response Relationship, Drug
Drug Design
Humans
Hypoglycemia / prevention & control
Hypoglycemic Agents / administration & dosage
Hypoglycemic Agents / chemical synthesis
Hypoglycemic Agents / therapeutic use*
Hypoglycemic Agents / toxicity
Insulin / metabolism
Male
Mice, Inbred ICR
Molecular Docking Simulation
Protein Binding
Receptors, G-Protein-Coupled / agonists*
Receptors, G-Protein-Coupled / chemistry
Receptors, G-Protein-Coupled / metabolism
Risk Assessment
Sulfones / chemistry
Sulfones / metabolism

Substances

Acetates
Benzofurans
Biphenyl Compounds
Ffar1 protein, mouse
Hypoglycemic Agents
Insulin
Receptors, G-Protein-Coupled
Sulfones
TAK-875