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PF-04937319 Sale

目录号 : GC36881

A glucokinase activator

PF-04937319 Chemical Structure

Cas No.:1245603-92-2

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产品描述

PF-04937319 is an activator of glucokinase (EC50s = 174, 407, and 269 nM for the recombinant human, rat, and dog enzymes, respectively).1 It increases glucose-induced insulin secretion in isolated rat islets when used at concentrations of 4 and 12 ?M.2 PF-04937319 (3-100 mg/kg) reduces postprandial plasma glucose levels in rats.

1.Petterson, J.C., Litchfield, J., Neef, N., et al.The relationship of glucokinase activator-induced hypoglycemia with arteriopathy, neuronal necrosis, and peripheral neuropathy in nonclinical studiesToxicol. Pathol.42(4)696-708(2014) 2.Pffefferkorn, J.A., Guzman-Perez, A., Oates, P.J., et al.Designing glucokinase activators with reduced hypoglycemia risk: Discovery of N,N-dimethyl-5-(2-methyl-6-((5-methylpyrazin-2-yl)-carbamoyl)benzofuran-4-yloxy)pyrimidine-2-carboxamide as a clinical candidate for the treatment of type 2 diabetes mellitusMedchemcomm.2828-839(2011)

Chemical Properties

Cas No. 1245603-92-2 SDF
Canonical SMILES O=C(C1=NC=C(OC2=C3C=C(C)OC3=CC(C(NC4=NC=C(C)N=C4)=O)=C2)C=N1)N(C)C
分子式 C22H20N6O4 分子量 432.43
溶解度 Soluble in DMSO 储存条件 Store at -20°C
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1 mg 5 mg 10 mg
1 mM 2.3125 mL 11.5626 mL 23.1251 mL
5 mM 0.4625 mL 2.3125 mL 4.625 mL
10 mM 0.2313 mL 1.1563 mL 2.3125 mL
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Research Update

Two dose-ranging studies with PF-04937319, a systemic partial activator of glucokinase, as add-on therapy to metformin in adults with type 2 diabetes

Diabetes Obes Metab 2015 Aug;17(8):751-9.PMID:25885172DOI:10.1111/dom.12474.

Aim: To assess the efficacy and safety of a range of doses of a systemic, partial, glucokinase activator, PF-04937319, as add-on therapy to metformin, in patients with type 2 diabetes mellitus (T2DM). Methods: Patients were randomized to once-daily PF-04937319 doses of 10, 50, 100 mg, or matching placebo (Study B1621002); or PF-04937319 doses of 3, 20, 50, 100 mg, or matching placebo (Study B1621007). Titrated glimepiride (Study B1621002) or sitagliptin (Study B1621007) were included in a double-dummy manner. The primary measure was change from baseline in glycated haemoglobin (HbA1c) at week 12. Key secondary measures included other glycaemic variables and safety and tolerability. Results: In the 639 patients randomized, the minimally efficacious PF-04937319 dose was identified as 50 mg once daily. At the highest PF-04937319 dose tested (100 mg), on average, a clinically significant reduction in HbA1c [-4.94 or -5.11 mmol/mol (-0.45 or -0.47%), placebo-adjusted], which was similar to that achieved with sitagliptin [-4.69 mmol/mol (-0.43%)] but lower than that achieved with titrated glimepiride [-9.07 mmol/mol (-0.83%)], was observed. At this dose, the effect on fasting plasma glucose was not consistent between the two studies (Study B1621002 vs Study B1621007: placebo-adjusted mean change of -0.83 vs +0.50 mmol/l). PF-04937319 was well tolerated at doses up to 100 mg. Hypoglycaemia was reported in 2.5% of patients (on placebo), 5.1% of patients (on PF-04937319 100 mg), 1.8% of patients (on sitagliptin) and 34.4% of patients (on titrated glimepiride). Conclusions: In patients on metformin monotherapy, the addition of a 100-mg dose of PF-04937319 improved glycaemic control and was well tolerated.

Glycemic Effect and Safety of a Systemic, Partial Glucokinase Activator, PF-04937319, in Patients With Type 2 Diabetes Mellitus Inadequately Controlled on Metformin-A Randomized, Crossover, Active-Controlled Study

Clin Pharmacol Drug Dev 2016 Nov;5(6):517-527.PMID:27870481DOI:10.1002/cpdd.261.

Glucokinase enhances glucose conversion to glucose-6-phosphate, causing glucose-stimulated insulin secretion from pancreatic β cells and increased hepatic glucose uptake. PF-04937319 is a partial glucokinase activator designed to maintain efficacy with reduced hypoglycemia risk. In this randomized, double-blind, double-dummy, 3-period crossover phase 1b study, patients aged 18-70 years with type 2 diabetes mellitus and on metformin received once-daily PF-04937319 (300 mg), split-dose PF-04937319 (150+100 mg; breakfast+lunch), or sitagliptin (100 mg once daily). The primary end point was day 14 weighted mean daily glucose (WMDG) change from period-specific baseline. Secondary end points included change from baseline in fasting plasma glucose, premeal C-peptide and insulin, and safety, including hypoglycemia frequency. Mean decrease from baseline in observed WMDG (mg/dL) was greater for PF-04937319 (split-dose, -31.24; once daily, -31.33) versus sitagliptin (-19.24). Using the integrated glucose red-cell HbA1c model, the observed WMDG effect with both PF-04937319 dosing regimens was projected to yield a clinically superior effect on mean glycated hemoglobin (HbA1c ; split-dose, -0.88%; once daily, -0.94%) compared with sitagliptin (-0.63%). There was no difference in premeal C-peptide or insulin levels, and although the effect on WMDG with both PF-04937319 regimens was similar, the split-dose regimen appeared to offer some advantage in safety and tolerability.

A novel Css-MRTpo approach to simulate oral plasma concentration-time profiles of the partial glucokinase activator PF-04937319 and its disproportionate N-demethylated metabolite in humans using chimeric mice with humanized livers

Xenobiotica 2020 Jul;50(7):761-768.PMID:31721621DOI:10.1080/00498254.2019.1693082.

A Css-MRTpo superposition method was devised to predict (retrospectively) oral plasma concentration-time profiles of PF-04937319 and its MIST-related metabolite, M1, in humans using chimeric mice with humanized liver.Original PK data were taken from a published report in which PF-04937319 and M1 were given to chimeric mice orally and/or intravenously. Human CL and Vss were predicted by single-species allometry and MRTiv,pred were calculated as Vss,pred/CL,pred. MRTpo,human were assumed to be MRTiv,pred plus MAT or mean metabolite formation time (MFT). Human Css was calculated by dividing the corrected oral dose by Vss,pred.Chronological sampling time and measured plasma concentrations were corrected by MRTpo,human and Css,human, respectively, and transformed to the corresponding values in humans.The obtained concentration-time profile of PF-04937319 was superimposed well with the observed data after single and repeated oral administration to humans. The transformed plasma concentration of M1 was somewhat lower than the observed value, but a slow increase of the simulated metabolite reflected gradual increase of observed M1 on Day 1. Transformed M1 gave an almost-flat concentration-time profile on Day 14, which was consistent with the curve observed in humans. Application of this novel method to other MIST-related compounds is discussed.

Simulation of human plasma concentration-time profiles of the partial glucokinase activator PF-04937319 and its disproportionate N-demethylated metabolite using humanized chimeric mice and semi-physiological pharmacokinetic modeling

Xenobiotica 2017 May;47(5):382-393.PMID:27389028DOI:10.1080/00498254.2016.1199063.

1. The partial glucokinase activator N,N-dimethyl-5-((2-methyl-6-((5-methylpyrazin-2-yl)carbamoyl)benzofuran-4-yl)oxy)pyrimidine-2-carboxamide (PF-04937319) is biotransformed in humans to N-methyl-5-((2-methyl-6-((5-methylpyrazin-2-yl)carbamoyl)benzofuran-4-yl)oxy)pyrimidine-2-carboxamide (M1), accounting for ∼65% of total exposure at steady state. 2. As the disproportionately abundant nature of M1 could not be reliably predicted from in vitro metabolism studies, we evaluated a chimeric mouse model with humanized liver on TK-NOG background for its ability to retrospectively predict human disposition of PF-04937319. Since livers of chimeric mice were enlarged by hyperplasia and contained remnant mouse hepatocytes, hepatic intrinsic clearances normalized for liver weight, metabolite formation and liver to plasma concentration ratios were plotted against the replacement index by human hepatocytes and extrapolated to those in the virtual chimeric mouse with 100% humanized liver. 3. Semi-physiological pharmacokinetic analyses using the above parameters revealed that simulated concentration curves of PF-04937319 and M1 were approximately superimposed with the observed clinical data in humans. 4. Finally, qualitative profiling of circulating metabolites in humanized chimeric mice dosed with PF-04937319 or M1 also revealed the presence of a carbinolamide metabolite, identified in the clinical study as a human-specific metabolite. The case study demonstrates that humanized chimeric mice may be potentially useful in preclinical discovery towards studying disproportionate or human-specific metabolism of drug candidates.

Metabolites in safety testing assessment in early clinical development: a case study with a glucokinase activator

Drug Metab Dispos 2014 Nov;42(11):1926-39.PMID:25142735DOI:10.1124/dmd.114.060087.

The present article summarizes Metabolites in Safety Testing (MIST) studies on a glucokinase activator, N,N-dimethyl-5-((2-methyl-6-((5-methylpyrazin-2-yl)carbamoyl)benzofuran-4-yl)oxy)pyrimidine-2-carboxamide (PF-04937319), which is under development for the treatment of type 2 diametes mellitus. Metabolic profiling in rat, dog, and human hepatocytes revealed that PF-04937319 is metabolized via oxidative (major) and hydrolytic pathways (minor). N-Demethylation to metabolite M1 [N-methyl-5-((2-methyl-6-((5-methylpyrazin-2-yl)carbamoyl)benzofuran-4-yl)oxy)pyrimidine-2-carboxamide] was the major metabolic fate of PF-04937319 in human (but not rat or dog) hepatocytes, and was catalyzed by CYP3A and CYP2C isoforms. Qualitative examination of circulating metabolites in humans at the 100- and 300-mg doses from a 14-day multiple dose study revealed unchanged parent drug and M1 as principal components. Because M1 accounted for 65% of the drug-related material at steady state, an authentic standard was synthesized and used for comparison of steady-state exposures in humans and the 3-month safety studies in rats and dogs at the no-observed-adverse-effect level. Although circulating levels of M1 were very low in beagle dogs and female rats, adequate coverage was obtained in terms of total maximal plasma concentration (∼7.7× and 1.8×) and area under the plasma concentration-time curve (AUC; 3.6× and 0.8× AUC) relative to the 100- and 300-mg doses, respectively, in male rats. Examination of primary pharmacology revealed M1 was less potent as a glucokinase activator than the parent drug (compound PF-04937319: EC50 = 0.17 μM; M1: EC50 = 4.69 μM). Furthermore, M1 did not inhibit major human P450 enzymes (IC50 > 30 μM), and was negative in the Salmonella Ames assay, with minimal off-target pharmacology, based on CEREP broad ligand profiling. Insights gained from this analysis should lead to a more efficient and focused development plan for fulfilling MIST requirements with PF-04937319.