Synthesis and biological evaluation of novel potent FFA1 agonists containing 2,3-dihydrobenzo[b][1,4]dioxine

Deyu Kong; Shimeng Guo; Yushe Yang; Bin Guo; Xin Xie; Wenhao Hu

doi:10.1016/j.bmcl.2019.01.014

Synthesis and biological evaluation of novel potent FFA1 agonists containing 2,3-dihydrobenzo[b][1,4]dioxine

Bioorg Med Chem Lett. 2019 Mar 15;29(6):848-852. doi: 10.1016/j.bmcl.2019.01.014. Epub 2019 Jan 17.

Authors

Deyu Kong¹, Shimeng Guo², Yushe Yang³, Bin Guo⁴, Xin Xie², Wenhao Hu⁵

Affiliations

¹ Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, School of Chemistry and Molecular Engineering, East China Normal University, Shanghai 200062, PR China; State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, PR China.
² CAS Key Laboratory of Receptor Research, The National Center for Drug Screening, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, PR China.
³ State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, PR China.
⁴ State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, PR China. Electronic address: guobin@simm.ac.cn.
⁵ Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, School of Chemistry and Molecular Engineering, East China Normal University, Shanghai 200062, PR China; School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China. Electronic address: huwh9@mail.sysu.edu.cn.

PMID: 30685095
DOI: 10.1016/j.bmcl.2019.01.014

Abstract

FFA1 (free fatty acid receptor 1) has emerged as an attractive antidiabetic target due to its role in mediating the enhancement of glucose-stimulated insulin secretion in pancreatic β cells with a low risk of hypoglycemia. Many reported FFA1 agonists possessed somewhat pharmacokinetic and/or safety issues. Herein, we describe the identification of 2,3-dihydrobenzo[b][1,4]dioxine as a novel scaffold for FFA1 agonists. Comprehensive structure-activity relationship study based on this scaffold led to the discovery of (S)-3-(4-(((S)-7-(4-methoxyphenyl)-2,3-dihydrobenzo [b][1,4]dioxin-2-yl)methoxy) phenyl)hex-4-ynoic acid (26k), which displayed a potent FFA1 agonistic activity and good pharmacokinetic profiles. Subsequent in vivo studies demonstrated that compound 26k significantly improved the glucose tolerance in ICR mice. In summary, compound 26k is a promising drug candidate for further investigation.

Keywords: 2,3-Dihydrobenzo[b][1,4]dioxine; FFA1 agonist; Insulin secretion; Type 2 diabetes mellitus.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Blood Glucose / drug effects
Dioxanes / chemical synthesis
Dioxanes / pharmacokinetics
Dioxanes / pharmacology*
HEK293 Cells
Humans
Hypoglycemic Agents / chemical synthesis
Hypoglycemic Agents / pharmacokinetics
Hypoglycemic Agents / pharmacology*
Male
Mice, Inbred ICR
Molecular Structure
Rats, Sprague-Dawley
Receptors, G-Protein-Coupled / agonists*
Structure-Activity Relationship

Substances

Blood Glucose
Dioxanes
Ffar1 protein, mouse
Hypoglycemic Agents
Receptors, G-Protein-Coupled