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 The most advanced clinical candidate, TAK-875, was withdrawn from phase III clinical trials due to liver safety issues.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.

CPL207280, a Novel G Protein-Coupled Receptor 40/Free Fatty Acid Receptor 1-Specific Agonist, Shows a Favorable Safety Profile and Exerts Antidiabetic Effects in Type 2 Diabetic Animals.

G protein-coupled receptor (GPR) 40 is a free fatty acid receptor mainly expressed in pancreatic ß-cells activated by medium- and long-chain fatty acids and regulating insulin secretion via an increase in cytosolic free calcium ([Ca2+]i). Activation of GPR40 in pancreatic ß-cells may improve glycemic control in type 2 diabetes through enhancement of glucose-stimulated insulin secretion. However, the most clinically advanced GPR40 agonist-TAK-875 (fasiglifam)-was withdrawn from phase III because of its hepatotoxicity resulting from the inhibition of pivotal bile acid transporters. Here, we present a new, potent CPL207280 agonist and compare it with fasiglifam in numerous in vitro and in vivo studies. CPL207280 showed greater potency than fasiglifam in a Ca2+ influx assay with a human GPR40 protein (EC50 = 80 vs. 270 nM, respectively). At the 10 µM concentration, it showed 3.9 times greater enhancement of glucose-stimulated insulin secretion in mouse MIN6 pancreatic ß-cells. In Wistar Han rats and C57BL6 mice challenged with glucose, CPL207280 stimulated 2.5 times greater insulin secretion without causing hypoglycemia at 10 mg/kg compared with fasiglifam. In three diabetic rat models, CPL207280 improved glucose tolerance and increased insulin area under the curve by 212%, 142%, and 347%, respectively. Evaluation of potential off-target activity (Safety47) and selectivity of CPL207280 (at 10 µM) did not show any significant off-target activity. We conclude that CPL207280 is a potent enhancer of glucose-stimulated insulin secretion in animal disease models with no risk of hypoglycemia at therapeutic doses. Therefore, we propose the CPL207280 compound as a compelling candidate for type 2 diabetes treatment. SIGNIFICANCE STATEMENT: GPR40 is a well-known and promising target for diabetes. This study is the first to show the safety and effects of CPL207280, a novel GPR40/free fatty acid receptor 1 agonist, on glucose homeostasis both in vitro and in vivo in different diabetic animal models. Therefore, we propose the CPL207280 compound as a novel, glucose-lowering agent, overcoming the unmet medical needs of patients with type 2 diabetes.