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Chemistry and Hypoglycemic Activity of GPR119 Agonist ZB-16.

ABSTRACT: This article is to highlight the chemical properties and primary pharmacology of novel GPR119 agonist ZB-16 and its analogs, which were rejected during the screening. Experiments were performed in vitro (specific activity, metabolism and cell toxicity) and in vivo (hypoglycemic activity and pharmacokinetics). ZB-16 exhibits nanomolar activity (EC50 = 7.3-9.7 nM) on target receptor GPR119 in vitro associated with hypoglycemic activity in vivo. In animals with streptozotocin-nicotinamide induced type 2 diabetes mellitus (STZ-NA T2D) daily oral dose of ZB-16 (1 mg/kg) or sitagliptin (10 mg/kg) for 28 days resulted in the reduction of blood glucose levels. The effects of ZB-16 were comparable to the hypoglycemic action of sitagliptin. ZB-16 demonstrated relatively low plasma exposition, high distribution volume, mild clearance and a prolonged half-life (more than 12 h). The present study demonstrates that the targeted search for selective GPR119 receptor agonists is a well-founded approach for developing novel drugs for the therapy of T2D. Based on the combination of high in vitro activity (compared to competitor standards), a useful ADME profile, distinct hypoglycemic activity which is comparable to the efficacy of sitagliptin in rats with experimental T2D, and the acceptable pharmacokinetic profile, we recommend the ZB-16 compound for further research.

SUBMITTER: Tyurenkov IN

PROVIDER: S-EPMC6156125 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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Chemistry and Hypoglycemic Activity of GPR119 Agonist ZB-16.

Tyurenkov Ivan N IN Kurkin Denis V DV Bakulin Dmitry A DA Volotova Elena V EV Morkovin Evgeny I EI Chafeev Mikhail A MA Karapetian Ruben N RN

Frontiers in endocrinology 20180919

This article is to highlight the chemical properties and primary pharmacology of novel GPR119 agonist ZB-16 and its analogs, which were rejected during the screening. Experiments were performed in vitro (specific activity, metabolism and cell toxicity) and in vivo (hypoglycemic activity and pharmacokinetics). ZB-16 exhibits nanomolar activity (EC50 = 7.3-9.7 nM) on target receptor GPR119 in vitro associated with hypoglycemic activity in vivo. In animals with streptozo ...[more]

PMID: 30283402

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Project description:UnlabelledGPR119 receptor agonists improve glucose metabolism and alter gut hormone profiles in animal models and healthy subjects. We therefore investigated the pharmacology of GSK1292263 (GSK263), a selective GPR119 agonist, in two randomized, placebo-controlled studies that enrolled subjects with type 2 diabetes. Study 1 had drug-naive subjects or subjects who had stopped their diabetic medications, and Study 2 had subjects taking metformin. GSK263 was administered as single (25-800 mg; n = 45) or multiple doses (100-600 mg/day for 14 days; n = 96). Placebo and sitagliptin 100 mg/day were administered as comparators. In Study 1, sitagliptin was co-administered with GSK263 or placebo on Day 14 of dosing. Oral glucose and meal challenges were used to assess the effects on plasma glucose, insulin, C-peptide, glucagon, peptide tyrosine-tyrosine (PYY), glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP). After 13 days of dosing, GSK263 significantly increased plasma total PYY levels by ∼ five-fold compared with placebo, reaching peak concentrations of ∼ 50 pM after each of the three standardized meals with the 300 mg BID dose. Co-dosing of GSK263 and metformin augmented peak concentrations to ∼ 100 pM at lunchtime. GSK263 had no effect on active or total GLP-1 or GIP, but co-dosing with metformin increased post-prandial total GLP-1, with little effect on active GLP-1. Sitagliptin increased active GLP-1, but caused a profound suppression of total PYY, GLP-1, and GIP when dosed alone or with GSK263. This suppression of peptides was reduced when sitagliptin was co-dosed with metformin. GSK263 had no significant effect on circulating glucose, insulin, C-peptide or glucagon levels. We conclude that GSK263 did not improve glucose control in type 2 diabetics, but it had profound effects on circulating PYY. The gut hormone effects of this GPR119 agonist were modulated when co-dosed with metformin and sitagliptin. Metformin may modulate negative feedback loops controlling the secretion of enteroendocrine peptides.Trial registrationClinicaltrials.gov NCT01119846 Clinicaltrials.gov NCT01128621.

Project description:Background:To investigate hypoglycemic activity and elucidate the active composition of the fruit blueberry (Vaccinium corymbosum). Methods:Methanol extracts of blueberry (MEB) were separated using a D101 macroporous resin column to yield quinic acid derivative (Fr.1)- and flavonoid (Fr.2)-rich fractions. The effects of the blueberry extracts on mRNA expression of GLUT-2 (glucose transporter type 2) and PPAR? (peroxisome proliferator-activated receptor-?), as well as on the activities of PPRE (peroxisome proliferator response element) and NF-?B were analyzed in LO2 normal liver cells. Real-time PCR was used to detect the expression of GLUT-2, PPAR?, TNF-?, IL-1?, and IL-6 mRNA. The PPRE and NF-?B activities were detected by a luciferase reporter assay. Western blotting was used to detect the levels of PPAR?, GLUT-2, and p65. The active compositions were isolated using various chromatography columns, and were analyzed by NMR. Results:mRNA and protein expression of GLUT-2 and PPAR? were significantly increased upon treatment with 400 ?g/mL extracts of blueberry (P<0.05). The PPRE activity was also significantly increased in a dose-dependent manner upon administration of MEB (P<0.05). Furthermore, the NF-?B activity induced by lipopolysaccharides was inhibited by MEB (P<0.05). No fraction separated from MEB exhibited PPRE activation or NF-?B inhibition activity. Blueberry extract may execute its hypoglycemic activity by stimulating expression of GLUT-2 and PPAR?, and by inhibiting the inflammatory pathway. Together, quinic acid derivatives and flavonoids may result in a synergistic effect. Fourteen phenolic acids, including eight flavonoids, four quinic acid derivatives, and two other phenolic acids, were isolated and identified, and caffeoylquinic acid derivatives and quercetin glycosides were found to be the major constituents of blueberry. Conclusion:Blueberry may have hypoglycemic activity that functions through synergistic effects with caffeoylquinic acid derivatives and quercetin glycosides.

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Chemistry and Hypoglycemic Activity of GPR119 Agonist ZB-16.

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Chemistry and Hypoglycemic Activity of GPR119 Agonist ZB-16.

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