GPR40 agonism is a promising new mechanism for the treatment of type 2 diabetes mellitus due to its ability to mediate glucose-stimulated insulin secretion (GSIS) from pancreatic β-cells. Tak-875 (fasiglifam, Takeda), the most clinically advanced GPR40 agonist, demonstrated clinical efficacy comparable to sulfonylureas without propensity to cause hypoglycemia and weight gain. However, fasiglifam was terminated in phase III trials due to liver toxicity. Most GPR40 agonists in the literature (including fasiglifam) have a carboxylic acid group, which may form an acyl glucuronide (AG), a reactive metabolite that may pose a risk for idiosyncratic drug toxicity. One way to mitigate this potential toxicity is to replace the carboxylic acid with a bioisostere. A novel series of GPR40 agonists containing a tetrazole as a carboxylic acid surrogate was identified. This series of compounds features a benzo[<i>b</i>]thiophene as the center ring, which is prone to oxidation during phase 1 metabolism. Following SAR optimization targeting GPR40 agonist activity and intrinsic clearance in microsomes (human and rat), potent and metabolically stable compounds were selected for in vivo evaluation. The compounds are efficacious at lowering blood glucose dose-dependently in a SD rat oGTT model. This class of non-carboxylate GPR40 agonists have the potential to be next generation glucose lowering agents without the threat of forming potentially reactive AG metabolites.

Discovery of novel benzo[<i>b</i>]thiophene tetrazoles as non-carboxylate GPR40 agonists

254th National Meeting (2017)

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Discovery of novel benzo[b]thiophene tetrazoles as non-carboxylate GPR40 agonists