Design, Synthesis And Biological Activity Of Novel GPR40 Agonist

The prevalence of type 2 diabetes (T2DM) has risen dramatically during recent decades. Despite some medications are available for treatment of T2DM, current therapy is often associated with weight gain and hypoglycemia, also with other adverse effects such as gastrointestinal discomfort. Therefore, there still remains a significant unmet need for new effective, oral anti-diabetic agents that improve glycemic control while maintaining an excellent safety profile.The G protein-coupled receptor 40 (GPR40, also known as FFA1) primarily expressed in pancreatic P-cells and enteroendocrine K and L cells of the small intestine. When activated by medium to long chain fatty acids, GPR40 elicits enhanced insulin secretion only in the presence of elevated glucose but does not affect insulin secretion at low glucose levels. This alluring mechanism to treat type 2 diabetes presents may serve as novel insulin secretagogues with no risk of hypoglycemia. In recent years, a number of potent GPR40 agonists have been reported and some of them have progressed to clinical trials, exemplified by TAK-875, AMG-837 and LY2881835. Unfortunately, these compounds have been terminated due to safety concerns.By analyzing their structures, we find that there is a common structural moiety of benzyloxy fragment in these compounds. This may cause potential safety concern due to benzaldehyde moiety resulted from metabolic oxidation at the benzyl position. Therefore, we designed and synthesized four series of 34 novel compounds by replacing the benzyloxy with different groups. Their structures were characterized by 1H NMR and MS. GPR40 agonistic activities were evaluated in HEK293 cells stably expressing human GPR40. The results indicated that most of compounds showed agonistic activity on GPR40 and compounds Ⅳ-h and Ⅳ-m were the most potent ones, with the EC50 0.266 μmol·L-1 and 0.268 μmol·L-1, respectively. Additionally, both compounds showed moderate metabolic stability, which manifested that they are worthy of further exploration.