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    PF-04991532
    PF-04991532

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    This product is for research use only, not for human use. We do not sell to patients.
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    InvivoChem Cat #: V4556
    CAS #: 1215197-37-7Purity ≥98%

    Description: PF-04991532 is a novel, potent, hepatoselective glucokinase activator with EC50 of 80 and 100 nM in human and rat, respectively. It is able to ameliorate hyperglycemia without causing hepatic steatosis in diabetic rats. Hyperglycemia resulting from type 2 diabetes mellitus (T2DM) is the main cause of diabetic complications such as retinopathy and neuropathy. A reduction in hyperglycemia has been shown to prevent these associated complications supporting the importance of glucose control. Glucokinase converts glucose to glucose-6-phosphate and determines glucose flux into the β-cells and hepatocytes. Since activation of glucokinase in β-cells is associated with increased risk of hypoglycemia, selectively activating hepatic glucokinase would reduce fasting and postprandial glucose with minimal risk of hypoglycemia. Previous studies have shown that hepatic glucokinase overexpression is able to restore glucose homeostasis in diabetic models; however, these overexpression experiments have also revealed that excessive increases in hepatic glucokinase activity may also cause hepatosteatosis. PF-04991532 reduced plasma glucose concentrations independent of changes in insulin concentrations in a dose-dependent manner both acutely and after 28 days of sub-chronic treatment. During a hyperglycemic clamp in Goto-Kakizaki rats, the glucose infusion rate was increased approximately 5-fold with PF-04991532. This increase in glucose infusion can be partially attributed to the 60% reduction in endogenous glucose production. While PF-04991532 induced dose-dependent increases in plasma triglyceride concentrations it had no effect on hepatic triglyceride concentrations in Goto-Kakizaki rats. Interestingly, PF-04991532 decreased intracellular AMP concentrations and increased hepatic futile cycling. These data suggest that hepatoselective glucokinase activation may offer glycemic control without inducing hepatic steatosis supporting the evaluation of tissue specific activators in clinical trials.

    ReferencesPLoS One. 2014 May 23;9(5):e97139.


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    PF-04991532

    Name: PF-04991532
    CAS#: 1215197-37-7
    Chemical Formula: C18H19F3N4O3
    Exact Mass: 396.1409
    Molecular Weight: 396.37
    Elemental Analysis: C, 54.54; H, 4.83; F, 14.38; N, 14.14; O, 12.11
    Storage-20℃ for 3 years in powder form
    -80℃ for 2 years in solvent
    Technical InformationSynonym: PF-04991532; PF 04991532; PF04991532; PF-4991532; PF4991532; PF 4991532.
    IUPAC/Chemical Name: (S)-6-(3-Cyclopentyl-2-(4-(trifluoromethyl)-1H-imidazol-1-yl)propanamido)nicotinic Acid
    InChi Key: GKMLFBRLRVQVJO-ZDUSSCGKSA-N
    InChi Code: InChI=1S/C18H19F3N4O3/c19-18(20,21)14-9-25(10-23-14)13(7-11-3-1-2-4-11)16(26)24-15-6-5-12(8-22-15)17(27)28/h5-6,8-11,13H,1-4,7H2,(H,27,28)(H,22,24,26)/t13-/m0/s1
    SMILES Code: O=C(O)C1=CN=C(NC([[email protected]@H](N2C=C(C(F)(F)F)N=C2)CC3CCCC3)=O)C=C1


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    PF-04991532


    PF-04991532 regulates glucose metabolism in primary rat hepatocytes.

    PF-04991532

    PF-04991532 effects on lipid metabolism and downstream hepatic metabolites.

     PF-04991532


    PF-04991532 increased hepatic futile cycling. The effect of hepatic glucokinase activation on G6Pase (A) and the loss of positional labeling (B) in primary rat hepatocytes.  (C). The increased substrate cycling decreased hepatic ATP concentrations as assessed by NMR (n = 6/group) (D) which in turn increased hepatic pAMPK/AMPK ratio (E) (n = 5/group).  2014 May 23;9(5):e97139.

     PF-04991532


    PF-04991532 improves glucose metabolism in rats. PF-04991532 increased the rate of glucose infusion in order to maintain hyperglycemia in Goto-Kakizaki rats (n = 6/group) (A) which can be attributed to the increased glucose disposal and decreased glucose production (n = 6/group) during steady state (B). PF-04991532 decreased plasma glucose in Goto-Kakizaki rats over 28 days of dosing (n = 6–8/group) (C) which was accompanied by an increase in plasma triglycerides at the highest dose (D).  2014 May 23;9(5):e97139.


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