TY - JOUR T1 - <strong>CPL207280 - a novel GPR40/FFA1-specific agonist shows a favorable safety profile and exerts anti-diabetic effects in type 2 diabetic animals.</strong> JF - Molecular Pharmacology JO - Mol Pharmacol DO - 10.1124/molpharm.121.000260 SP - MOLPHARM-AR-2021-000260 AU - Katarzyna Bazydlo-Guzenda AU - Pawel Buda AU - Mikolaj Matloka AU - Mateusz Mach AU - Filip Stelmach AU - Radoslaw Dzida AU - Damian Smuga AU - Joanna Hucz-Kalitowska AU - Malgorzata Teska-Kaminska AU - Varvara Vialichka AU - Krzysztof Dubiel AU - Bozena Kaminska AU - Maciej Wieczorek AU - Jerzy Pieczykolan Y1 - 2021/01/01 UR - http://molpharm.aspetjournals.org/content/early/2021/08/03/molpharm.121.000260.abstract N2 - G protein-coupled receptor 40 (GPR40) 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 However, the most clinically advanced GPR40 agonist - TAK-875 (fasiglifam) - was withdrawn from phase III due to its hepatotoxicity resulting from the inhibition of pivotal bile acid transporters.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 Ca2+ influx assay with a hGPR40 protein (EC50=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{trade mark, serif}) 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/FFA1 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 T2D patients' unmet medical needs. ER -