Discovery and development of CPL207280 as new GPR40/FFA1 agonist

Due to a unique mechanism that limits the possibility of hypoglycemia, the free fatty acid receptor (FFA1) is an attractive target for the treatment of type 2 diabetes. So far, however, none of the promising agonists have been able to enter the market. The most advanced clinical candidate, TAK-875, was withdrawn from phase III clinical trials due to liver safety issues. In this article, we describe the key aspects leading to the discovery of CPL207280 (13), the design of which focused on long-term safety. The introduction of small, nature-inspired acyclic structural fragments resulted in compounds with retained high potency and a satisfactory pharmacokinetic profile. Optimized synthesis and upscaling provided a stable, solid form of CPL207280-51 (45) with the properties required for the toxicology studies and ongoing clinical trials. (C) 2021 Elsevier Masson SAS. All rights reserved.

Automated summary

The study focuses on the potential of the free fatty acid receptor (FFA1) for treating type 2 diabetes, but no successful agonists have entered the market yet. The discovery of CPL207280 was driven by the design for long-term safety, resulting in stable compounds with satisfactory pharmacokinetic profiles.