Design and optimization of 2, 3-dihydrobenzo[b][1, 4]dioxine propanoic acids as novel GPR40 agonists with improved pharmacokinetic and safety profiles. Issue 22 (1st December 2018)

• Record Type: Journal Article
• Authors: Guo, Bin; Guo, Shimeng; Huang, Jing; Li, Jingya; Li, Jia; Chen, Qian; Zhou, Xianli; Xie, Xin; Yang, Yushe
• Is Part Of: Bioorganic & medicinal chemistry. Volume 26:Issue 22(2018)
• Page Start: 5780
• Page End: 5791
• Publication Date: 2018-12-01
• Subjects: GPR40 agonist -- 2, 3-Dihydrobenzo[b][1, 4]dioxine -- Insulin secretion -- Type 2 diabetes mellitus; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; Biochemistry -- Periodicals; Chemistry, Clinical -- Periodicals; Chemistry, Organic -- Periodicals; Chimie bio-organique -- Périodiques; Chimie pharmaceutique -- Périodiques; 615.19
• DOI: 10.1016/j.bmc.2018.10.019
• Languages: English
• ISSNs: 0968-0896

Abstract

Graphical abstract: Highlights: A number of 2, 3-dihydrobenzo[b][1, 4]dioxine phenylpropanoic acid derivatives were designed and synthesized. These compounds were evaluated for their in vitro GPR40 agonistic activities and selectivity. Most analogues showed potent agonistic activities and high selectivity. Compound 40a displayed improved metabolic stability and oral absorption. 40a exhibited lower hepatobiliary transporter inhibition and favorable druggability compared with TAK-875. Abstract: GPR40 has become a new potential therapeutic target for the treatment of diabetes due to its role in mediating the enhancement of glucose-stimulated insulin secretion in pancreatic β cells with a low risk of hypoglycemia. As an effort to extend the chemical space and identify structurally distinct GPR40 agonists with improved liver safety, a novel series of fused-ring phenyl propanoic acid analogues were designed. Comprehensive structure-activity relationship studies around novel scaffolds were conducted and led to several analogues exhibited potent GPR40 agonistic activities and high selectivity against other fatty acid receptors. Further evaluation of pharmacokinetic (PK) profiles and in vivo efficacy identified compound40a with excellent PK properties and significant glucose-lowering efficacy during an oral glucose tolerance test. In addition, compound40a displayed lower hepatobiliary transporter inhibition and favorable druggability. All results indicate that compound40a is a promising candidate for further development.