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

Abstract

G protein-coupled receptor 40 (GPR40) is a free fatty acid receptor mainly expressed in pancreatic βcells activated by medium-and long-chain fatty acids and regulating insulin secretion via an increase in cytosolic free calcium ([Ca 2+ ] i ). Activation of GPR40 in pancreatic β-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 However, the most clinically advanced GPR40 agonist -TAK-875 (fasiglifam)was withdrawn from phase III due to its hepatotoxicity resulting from the inhibition of pivotal bile acid transporters.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 Ca 2+ influx assay with a hGPR40 protein (EC 50 =80 vs. 270 nM, respectively). At the 10 µM concentration, it showed 3.9 times greater enhancement of GSIS in mouse MIN6 pancreatic β 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.

First‐in‐human study of CPL207280, a novel G‐protein‐coupled receptor 40/free fatty acid receptor 1 agonist, in healthy volunteers after single and multiple administration

“…The low to moderate inter‐subject variability in PK parameters observed in the MAD study suggests that CPL207280 could be characterized by predictable PK and potential clinical effects in a target population. The non‐clinical data show that, sharing similar plasma protein binding values >95% (data not shown), CPL207280 is three times more effective than fasiglifam in activating the GPR40 receptor in vitro and in vivo 11 . Therefore, we hypothesize that the PK profile of CPL207280 is balanced and should be sufficient to improve glycaemia without any signs of toxicity after once‐daily administration in future clinical trials.…”

“…In our previous work, we described the preclinical development of CPL207280, a new, potent and highly selective GPR40 agonist 11 and a potential precursor of a novel class of antidiabetic agents. Its modified structure, developed as a metformin (N, N 0 -dimethylbiguanide) salt, maintains potency and bioavailability with respect to fasiglifam.…”

“…12 Preclinical studies showed that CPL207280 improved glucose tolerance via glucose-dependent insulin secretion in diabetic animal models without risk of hepatotoxicity. 11,13 The formulation development resulted in a sustained-release (SR) dosage form. 14 Here, we report the results of a first-in-human study in healthy subjects to evaluate the safety, tolerability, and pharmacokinetic (PK) profile of CPL207280 after single and multiple doses.…”

“…Its reduced molecular weight and lipophilicity minimized the risk of potential side effects, including drug‐induced liver injury (DILI) 12 . Preclinical studies showed that CPL207280 improved glucose tolerance via glucose‐dependent insulin secretion in diabetic animal models without risk of hepatotoxicity 11,13 . The formulation development resulted in a sustained‐release (SR) dosage form 14 …”

Learn from failures and stay hopeful to GPR40, a GPCR target with robust efficacy, for therapy of metabolic disorders

“…It showed a more robust induction of insulin and improved glucose tolerance than TAK-875 in preclinical models. It also appeared to have a better safety profile than TAK-875 in rats and monkeys ( Bazydlo-Guzenda et al, 2021b ). Phase I trial of CPL207280 was safe and well tolerated with no serious AEs in healthy participants.…”