Design, synthesis and structure–activity relationship studies of novel phenoxyacetamide-based free fatty acid receptor 1 agonists for the treatment of type 2 diabetes. Issue 20 (15th October 2015)

• Record Type: Journal Article
• Authors: Li, Zheng; Wang, Xuekun; Xu, Xue; Yang, Jianyong; Qiu, Qianqian; Qiang, Hao; Huang, Wenlong; Qian, Hai
• Is Part Of: Bioorganic & medicinal chemistry. Volume 23:Issue 20(2015)
• Page Start: 6666
• Page End: 6672
• Publication Date: 2015-10-15
• Subjects: FFA1 agonist -- OGTT -- Amide linkers -- Ligand efficiency -- Type 2 diabetes; 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.2015.09.010
• Languages: English
• ISSNs: 0968-0896

Abstract

Graphical abstract: Abstract: The free fatty acid receptor 1 (FFA1) has attracted extensive attention as a novel antidiabetic target in the last decade. Several FFA1 agonists reported in the literature have been suffered from relatively high molecular weight and lipophilicity. We have previously reported the FFA1 agonist1 . Based on the common amide structural characteristic of SAR1 and NIH screened compound, we here describe the continued structure–activity exploration to decrease the molecular weight and lipophilicity of the compound1 series by converting various amide linkers. All of these efforts lead to the discovery of the preferable lead compound18, a compound with considerable agonistic activity, high LE and LLE values, lower lipophilicity than previously reported agonists, and appreciable efficacy on glucose tolerance in both normal and type 2 diabetic mice.