Design, synthesis and structure-activity relationship studies of novel free fatty acid receptor 1 agonists bearing amide linker

Bioorg Med Chem. 2017 Apr 15;25(8):2445-2450. doi: 10.1016/j.bmc.2017.03.001. Epub 2017 Mar 2.

Abstract

The free fatty acid receptor 1 (FFA1/GPR40) has attracted extensive attention as a novel antidiabetic target. Aiming to explore the chemical space of FFA1 agonists, a new series of lead compounds with amide linker were designed and synthesized by combining the scaffolds of NIH screened lead compound 1 and GW9508. Among them, the optimal lead compound 17 exhibited a considerable agonistic activity (45.78%) compared to the NIH screened compound 1 (15.32%). During OGTT in normal mice, the compound 17 revealed a significant glucose-lowering effect (-23.7%) at the dose of 50mg/kg, proximity to the hypoglycemic effect (-27.8%) of Metformin (200mg/kg). In addition, the compound 17 (100mg/kg) also exhibited a significant improvement in glucose tolerance with a 29.1% reduction of glucose AUC0-2h in type 2 diabetic mice. All of these results indicated that compound 17 was considered to be a promising lead structure suitable for further optimization.

Keywords: Amide; FFA1 agonist; GPR40; Hybrid; Type 2 diabetes.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amides / chemistry*
  • Animals
  • Area Under Curve
  • Blood Glucose / analysis
  • Diabetes Mellitus, Experimental / drug therapy
  • Diabetes Mellitus, Type 2 / drug therapy
  • Fatty Acids, Nonesterified / agonists*
  • Glucose Tolerance Test
  • Mice
  • Structure-Activity Relationship

Substances

  • Amides
  • Blood Glucose
  • Fatty Acids, Nonesterified