Chronic treatment with novel GPR40 agonists improve whole-body glucose metabolism based on the glucose-dependent insulin secretion.

GPR40 is a free fatty acid receptor that has been shown to regulate glucose-dependent insulin secretion. This study aimed to discover novel GPR40 agonists and investigate the whole-body effect on glucose metabolism of GPR40 activation using these novel GPR40 agonists. To identify novel GPR40-specific agonists, we conducted high-throughput chemical compound screening and evaluated glucose-dependent insulin secretion. To investigate the whole-body effect on glucose metabolism of GPR40 activation, we conducted repeat administration of the novel GPR40 agonists to diabetic model ob/ob mice and evaluated metabolic parameters. To characterize the effect of the novel GPR40 agonists more deeply, we conducted an insulin tolerance test and a euglycemic-hyperinsulinemic clamp test. As a result, we discovered the novel GPR40-specific agonists, including AS2034178 [bis{2-[(4-{[4'-(2-hydroxyethoxy)-2'-methyl[1,1'-biphenyl]-3-yl]methoxy}phenyl)methyl]-3,5-dioxo-1,2,4-oxadiazolidin-4-ide} tetrahydrate], and found that its exhibited glucose-dependent insulin secretion enhancement both in vitro and in vivo. In addition, the compounds also decreased plasma glucose and HbA1c levels after repeat administration to ob/ob mice, with favorable oral absorption and pharmacokinetics. Repeat administration of AS2034178 enhanced insulin sensitivity in an insulin tolerance test and a euglycemic-hyperinsulinemic clamp test. These results indicate that improvement of glucose-dependent insulin secretion leads the improvement of whole-body glucose metabolism chronically. In conclusion, AS2034178 and other GPR40 agonists may become useful therapeutics in the treatment of type 2 diabetes mellitus.

A comparison of pharmacokinetics between humans and monkeys.

To verify the availability of pharmacokinetic parameters in cynomolgus monkeys, hepatic availability (Fh) and the fraction absorbed multiplied by intestinal availability (FaFg) were evaluated to determine their contributions to absolute bioavailability (F) after intravenous and oral administrations. These results were compared with those for humans using 13 commercial drugs for which human pharmacokinetic parameters have been reported. In addition, in vitro studies of these drugs, including membrane permeability, intrinsic clearance, and p-glycoprotein affinity, were performed to classify the drugs on the basis of their pharmacokinetic properties. In the present study, monkeys had a markedly lower F than humans for 8 of 13 drugs. Although there were no obvious differences in Fh between humans and monkeys, a remarkable species difference in FaFg was observed. Subsequently, we compared the FaFg values for monkeys with the in vitro pharmacokinetic properties of each drug. No obvious FaFg differences were observed between humans and monkeys for drugs that undergo almost no in vivo metabolism. In contrast, low FaFg were observed in monkeys for drugs that undergo relatively high metabolism in monkeys. These results suggest that first-pass intestinal metabolism is greater in cynomolgus monkeys than in humans, and that bioavailability in cynomolgus monkeys after oral administration is unsuitable for predicting pharmacokinetics in humans. In addition, a rough correlation was also observed between in vitro metabolic stability and Fg in humans, possibly indicating the potential for Fg prediction in humans using only in vitro parameters after slight modification of the evaluation system for in vitro intestinal metabolism.