Synthesis and biological evaluation of novel potent FFA1 agonists containing 2,3-dihydrobenzo[b][1,4]dioxine.
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.
['Kong|Deyu|D|', 'Guo|Shimeng|S|', 'Yang|Yushe|Y|', 'Guo|Bin|B|', 'Xie|Xin|X|', 'Hu|Wenhao|W|']
D000818:Animals D001786:Blood Glucose D004146:Dioxanes D057809:HEK293 Cells D006801:Humans D007004:Hypoglycemic Agents D008297:Male D008813:Mice, Inbred ICR D015394:Molecular Structure D017207:Rats, Sprague-Dawley D043562:Receptors, G-Protein-Coupled D013329:Structure-Activity Relationship
FFA1 agonist 2,3-Dihydrobenzo[b][1,4]dioxine Insulin secretion Type 2 diabetes mellitus