GPR40 is a G protein-coupled receptor that is predominantly expressed in pancreatic β-cells. GPR40 agonists stimulate insulin secretion in the presence of high glucose concentration. On the basis of this mechanism, GPR40 agonists are possible novel insulin secretagogues with reduced or no risk of hypoglycemia. The improvement of in vitro activity and metabolic stability of compound 1 led to the discovery of 13, (3S)-3-ethoxy-3-(4-{[(1R)-4-(trifluoromethyl)-2,3-dihydro-1H-inden-1-yl]oxy}phenyl)propanoic acid, as a potent and orally available GPR40 agonist. Compound 13 (DS-1558) was found to have potent glucose lowering effects during an oral glucose tolerance test in ZDF rats. KEYWORDS: GPR40, agonist, insulin secretagogue, diabetes, glucose lowering T ype 2 diabetes is a metabolic disorder characterized by impaired glucose homeostasis caused by insufficient insulin secretion or insulin resistance. The number of diabetics has been increasing all over the world and has reached nearly 350 million.1,2 Current common therapies include the use of insulin injections, sulfonylureas, metformin, and glinides. 3,4 Most of them are associated with problems such as weight gain, risk of hypoglycemia, and lack of sustained efficacy. 5−9 Lately, glucose-dependent insulin secretagogues, such as GPR119 10 and GPR142 11 agonists, have attracted attention as alternative treatments for diabetes. Among them, DPP-IV inhibitors enhancing the activity of GLP-1 have already been widely used. Most recently, SGLT2 inhibitors that inhibit the reuptake of urinal sugar have been developed as hypoglycemic agents with low risk of weight gain.GPR40 is primarily expressed in pancreatic β-cells and activated by long-chain free fatty acids, resulting in enhancement of glucose-stimulated insulin secretion (GSIS) dependent on elevated glucose levels.12−17 On the basis of this GSIS mechanism, GPR40 has also received considerable attention as a novel therapeutic target for type 2 diabetes because of its low risk of hypoglycemia. 18,19 Recently, several groups have reported GPR40 agonists that contain acidic moieties such as a carboxylic acid or thiazolidinedione (Figure 1). 20−28 We have also identified 3-ethoxypropanoic acid 1 as a promising lead compound (Figure 2).
29Herein we describe the lead optimization of 1 to discover (3S)-3-ethoxy-3-(4-{[(1R)-4-(trifluoromethyl)-2,3-dihydro-1H-inden-1-yl]oxy}phenyl)propanoic acid (13), a potent and orally available GPR40 agonist.Although compound 1 showed a glucose lowering effect in rats after oral administration, its half-life was very short (Table 2). High in vivo clearance of 1 was probably due to metabolic oxidation at the benzyl position because we detected a glutathione (GSH) adduct of 2-methylbenzaldehyde, a putative metabolite of 1, from a GSH trapping assay in human liver microsomes. Therefore, we designed the cyclized compounds