Activation of GPR40 (G-protein coupled receptor 40) in pancreatic beta cells may improve glycaemic control in type 2 diabetes (T2D) through enhancement of glucose-stimulated insulin secretion (GSIS). However, the most clinically advanced GPR40 agonist fasiglifam was withdrawn from phase 3 for its hepatotoxicity resulting presumably from the inhibition of pivotal bile acid transporters. Here we present a potent CPL207-280CA agonist devoid of fasiglifams drawbacks as numerous comparative in vitro and in vivo studies revealed. In Ca2+ influx assay (hGPR40), CPL207-280CA showed higher efficacy than fasiglifam (EC50=70 vs. 250 nM respectively). At 10 µM it showed 3.9-times greater enhancement of GSIS in MIN6 cells. Similarly, in Spraque Dawley (SD) rats and C57BL6 mice challenged with glucose, CPL207-280CA compared with fasiglifam at 10 mg/kg stimulated insulin secretion 2.5-times greater (AUC), without causing hypoglycaemia. CPL207-280CA (at 10 µM) subjected to off-targets’ (Safety47TM, BioMAP) and selectivity analysis showed no off-target activity, as well as in MIN6 and HepG2 cells it exhibited broader range of non toxic doses than its comparator. Finally, in hepatobiliary transporters inhibitory assays (carried out in 10 crucial transporters), CPL207-280CA displayed considerably less propensity than fasiglifam, as favourable IC50 values indicate e.g.: human bile salt export pump (Bsep), >100 and 30 µM; multidrug resistance-associated protein 2 (Mrp2), N.D. and 48 µM; organic anion transporting polypeptide (OATP) 1B1, 17.9 and 0.49 µM; organic anion transporting polypeptide (OATP) 1B3, 43 and 3.4 µM; organic anion transporting polypeptide (OATP) 1A2, 118 and 10.6 µM respectively. We conclude that CPL207-280CA is a potent enhancer of GSIS in model animals, which brings no risk of hypoglycaemia and substantially less risk of hepatotoxicity at therapeutic doses. Therefore we propose CPL207-280CA compound as an effective and safe candidate for the T2D treatment.


K. Bazydlo: Employee; Self; Celon Pharma S.A. P. Buda: Employee; Self; CelonPharma S.A. M. Mach: Employee; Self; Celon Pharma S.A. R. Dzida: Employee; Self; Celon Pharma S.A. F. Stelmach: Employee; Self; Celon Pharma S.A. K.K. Dubiel: Employee; Self; Celon Pharma S.A. J.S. Pieczykolan: Employee; Self; Celon Pharma.S.A. M. Wieczorek: Board Member; Self; Celon Pharma S.A..

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