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.

Katarzyna Bazydlo-Guzenda,Joanna Hucz-Kalitowska,Krzysztof Dubiel,Varvara Vialichka,Pawel Buda,Jerzy Pieczykolan,Malgorzata Teska-Kaminska,Filip Stelmach,Damian Smuga,Bozena Kaminska,Maciej Wieczorek,Radoslaw Dzida,Mikolaj Matloka,Mateusz Mach

doi:10.1124/molpharm.121.000260

Abstract

G protein-coupled receptor (GPR) 40 is a free fatty acid receptor mainly expressed in pancreatic β-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 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 However, the most clinically advanced GPR40 agonist-TAK-875 (fasiglifam)-was withdrawn from phase III because of its hepatotoxicity resulting from the inhibition of pivotal bile acid transporters.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 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. 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.

Highlights

G protein–coupled receptor (GPR) 40 is a free fatty acid receptor mainly expressed in pancreatic b-cells (Itoh and Hinuma, 2005; Schnell et al, 2007)
Characteristics of CPL207280 Activity In Vitro After reviewing the compound library in search of GPR40 agonists, we identified CPL207280 (Fig. 1) as the lead structure for further development
The present results showed that CPL207280 increased Ca21 in CHO cells expressing human GPR40 with a higher potency than TAK-875 and had no impact on cells expressing related receptors: GPR41 (FFA2), GPR43 (FFA3), GPR55, GPR119, GPR120, GPR142 (Table 1)

Summary

Introduction

G protein–coupled receptor (GPR) 40 (or FFA1) is a free fatty acid receptor mainly expressed in pancreatic b-cells (Itoh and Hinuma, 2005; Schnell et al, 2007). It mediates signaling from free fatty acid (FFA) to modulate glucose-stimulated insulin secretion (GSIS) (Briscoe et al, 2003; Itoh et al, 2003). Glucose dependence of the GPR40 insulinotropic activity is important from the clinical perspective. It may allow prevention of the main adverse effect (iatrogenic hypoglycemia) of the currently popular sulfonylureas (SUs), which stimulates insulin secretion irrespective of glucose levels (Sola et al, 2015). This, in turn, leads to a Ca21 overload and propels b-cell dysfunction, leading to cell death (Iwakura et al, 2000)

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Conclusion