ZYDG2, a Potent, Selective, and Safe GPR40 Agonist for Treatment of Type 2 Diabetes

Abstract

GPR40 is a G-protein-coupled receptor predominantly expressed in pancreatic β-cells. Agonists of GPR40 are known to stimulate insulin secretion and reduces circulating glucose levels in a glucose-dependent manner. TAK-875, a GPR40 small molecule agonist developed by Takeda Pharmaceuticals showed antidiabetic efficacy in animals and humans, but its development was terminated in phase 3 due to adverse liver effects. ZYDG2 is a safer GPR40 agonist that has shown desirable profile in preclinical studies. ZYDG2 was identified as a potent and selective agonist for GPR40, exhibiting EC50 of 13 nM and 41 nM for hGPR40, in HEK-293 cell-based Ca2+ mobilization assay and IP1 ELISA assays respectively. It increased insulin secretion and showed dose-dependent improvement in glucose tolerance test in n-STZ Wistar rats, DIO mice and db/db mice. It also showed anti-hyperglycemic effects in rats unresponsive to sulfonylureas. No tachyphylaxis was observed after repeated administration for 15 weeks in n-STZ rats. ZYDG2 showed glucose-stimulated insulin secretion as revealed by significant increase in glucose infusion rate in hyperglycemic clamp study using SD rats. ZYDG2 treatment was associated with significant rise in plasma total GLP1 levels in nondiabetic and diabetic animal models which was not observed in case of TAK-875. Since TAK-875 was terminated due to hepatotoxicity associated with bile acid transporter inhibition, this aspect was studied in details. TAK-875 inhibited the hBSEP and hMRP2 at efficacy concentrations whereas ZYDG2 does not show any inhibition (up to 300 µM) for hBSEP and hMRP2. TAK-875 also showed significantly increased cholic acid levels in Sprague Dawley rat which was not shown by ZYDG2. The maximum tolerated dose for ZYDG2 was 2000 mg/kg and 28 days NOAEL was 300 mg/kg. This clearly demonstrates that ZYDG2 has a great potential to become a safe and effective candidate for treatment of type 2 diabetes. Disclosure M.R. Jain: None. S.R. Giri: None. C.J. Trivedi: None. B.B. Bhoi: None. A.C. Rath: None. R.M. Rathod: None. R. Sundar: None. D. Bandyopadhyay: None. R. Ramdhave: None. G.D. Patel: None. B.K. Srivastava: None. R.C. Desai: None.

Evaluation of the hepatotoxicity of the novel GPR40 (FFAR1) agonist CPL207280 in the rat and monkey

“…Similarly, in the other studies of ZYDG2 or HD-6277 researchers performed comparison of liver toxicity (including inhibition of bile transporters and toxicology study in rats and dogs, respectively) with that of TAK-875. However, the in vivo studies missed an equal drug-exposures to enable fair toxicity comparison [ 43 , 44 ]. Drug-exposure divergences result from different absorption, distribution, metabolism, and excretion (ADME) of specific agonists in the studied animal species.…”

Activating Effects of Phenolics from Apache Red Zea mays L. on Free Fatty Acid Receptor 1 and Glucokinase Evaluated with a Dual Culture System with Epithelial, Pancreatic, and Liver Cells

“…GPR40 became interesting as a potential molecular target to reduce type 2 diabetes complications as a result of its insulinotropic effects . In past years, GPR40 was thought to participate in lipotoxicity processes, and it was inconclusive whether it was desired or not to activate it in certain metabolic conditions .…”

“…GPR40 became interesting as a potential molecular target to reduce type 2 diabetes complications as a result of its insulinotropic effects. 5 In past years, GPR40 was thought to participate in lipotoxicity processes, and it was inconclusive whether it was desired or not to activate it in certain metabolic conditions. 6 However, recent studies using transgenic GPR40 −/− C57BL/6 mice demonstrated that its activation increases insulin secretion, improves glucose tolerance, and might even protect pancreatic cells from lipotoxicity.…”