Optimization of (2,3-Dihydro-1-benzofuran-3-yl)acetic Acids: Discovery of a Non-Free Fatty Acid-Like, Highly Bioavailable G Protein-Coupled Receptor 40/Free Fatty Acid Receptor 1 Agonist as a Glucose-Dependent Insulinotropic Agent

G protein-coupled receptor 40 (GPR40)/free fatty acid receptor 1 (FFA1) is a free fatty acid (FFA) receptor that mediates FFA-amplified glucose-stimulated insulin secretion in pancreatic β-cells. We previously identified (2,3-dihydro-1-benzofuran-3-yl)­acetic acid derivative <b>2</b> as a candidate, but it had relatively high lipophilicity. Adding a polar functional group on <b>2</b> yielded several compounds with lower lipophilicity and little effect on caspase-3/7 activity at 30 μM (a marker of toxicity in human HepG2 hepatocytes). Three optimized compounds showed promising pharmacokinetic profiles with good in vivo effects. Of these, compound <b>16</b> had the lowest lipophilicity. Metabolic analysis of <b>16</b> showed a long-acting PK profile due to high resistance to β-oxidation. Oral administration of <b>16</b> significantly reduced plasma glucose excursion and increased insulin secretion during an OGTT in type 2 diabetic rats. Compound <b>16</b> (TAK-875) is being evaluated in human clinical trials for the treatment of type 2 diabetes