| Identification | Back Directory | [Name]
PF-06424439 | [CAS]
1469284-78-3 | [Synonyms]
Methanone, [(3R)-1-[2-[1-(4-chloro-1H-pyrazol-1-yl)cyclopropyl]-3H-imidazo[4,5-b]pyridin-5-yl]-3-piperidinyl]-1-pyrrolidinyl- | [Molecular Formula]
C22H26ClN7O | [MDL Number]
MFCD32182612 | [MOL File]
1469284-78-3.mol | [Molecular Weight]
439.94 |
| Chemical Properties | Back Directory | [Boiling point ]
752.8±60.0 °C(Predicted) | [density ]
1.57±0.1 g/cm3(Predicted) | [solubility ]
DMSO:70.0(Max Conc. mg/mL);159.11(Max Conc. mM)
H2O:70.0(Max Conc. mg/mL);159.11(Max Conc. mM) | [form ]
Solid | [pka]
12.11±0.40(Predicted) | [color ]
White to off-white |
| Hazard Information | Back Directory | [Description]
PF-06424439 is a potent and selective Diacylglycerol Acyltransferase 2 ( DGAT2) inhibitor with DGAT2 IC50 ± SEM (nM) (humarat/dog) 14 ± 1/38 ± 4/16 ± 1. PF-06424439 demonstrated excellent ADMET properties and decreased circulating and hepatic lipids when orally administered to dyslipidemic rodent models. PF-06424439 inhibited DGAT2 of different species (human, rat, and dog) with similar potency. Among related acyltransferases, no significant inhibition was observed for PF-06424439 (up to 50 μM) against human MGAT2 or MGAT3, DGAT1, or mouse MGAT1, indicating a high selectivity (>2000-fold) against these enzymes. | [Uses]
PF-06424439 is an oral, potent and selective imidazopyridine diacylglycerol acyltransferase 2 (DGAT2) inhibitor with an IC50 of 14 nM[1]. PF-06424439 is slowly reversible, time-dependent inhibitor, which inhibits DGAT2 in a noncompetitive mode with respect to the acyl-CoA substrate[2]. | [in vitro]
The effect of PF-06424439, a selective DGAT2 inhibitor, on MCF7 breast cancer cells exposed to X-rays was evaluated. The results demonstrated that 72 h of PF-06424439 treatment reduced LD (lipid droplets) content and inhibited cell migration, without affecting cell proliferation. Interestingly, PF-06424439 pre-treatment followed by radiation was able to enhance radiosensitivity of MCF7 cells. These findings suggest that PF-06424439 pre-treatment coupled to X-ray exposure might potentiate breast cancer cell radiosensitivity and potentially improve the radiotherapy effectiveness. _x000D_
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Reference: Int J Mol Sci. 2021 Sep 18;22(18):10102. https://pubmed.ncbi.nlm.nih.gov/34576263/ | [in vivo]
The effects of DGAT1 and DGAT2 inhibition, alone or in combination, on dietary TAG absorption and diarrhea in mice were investigated by using a selective DGAT1 inhibitor (PF-04620110) and DGAT2 inhibitor (PF-06424439). To further understand relationship between diarrhea and changes in DGAT activity, we examined dose‐dependent effects of DGAT inhibitors in mice. Simultaneous administration of a lower‐dose DGAT1 (0.03 mg/kg) inhibitor, which did not produce maximal effects on intestinal TAG secretion, and the DGAT2 inhibitors significantly decreased plasma radioactivity. These findings suggest that DGAT-mediated intestinal TAG synthesis is a vital step for maintaining intestinal barrier integrity under HFD (high-fat diet) feeding._x000D_
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Reference: Physiol Rep. 2020 Aug;8(15):e14542. https://pubmed.ncbi.nlm.nih.gov/32786057/ | [target]
PF-06424439 is a selective imidazopyridine diacylglycerol acyltransferase 2 (DGAT2) inhibitor with an IC50 of 14 nM that is a slowly reversible, time-dependent inhibitor, which inhibits DGAT2 in a noncompetitive mode with respect to the acyl-CoA substrate. | [References]
[1] Futatsugi K, et al. Discovery and Optimization of Imidazopyridine-Based Inhibitors of Diacylglycerol Acyltransferase 2 (DGAT2). J Med Chem. 2015 Sep 24;58(18):7173-85. DOI:10.1021/acs.jmedchem.5b01006
[2] Pabst B, et al. Mechanistic Characterization of Long Residence Time Inhibitors of Diacylglycerol Acyltransferase 2 (DGAT2). Biochemistry. 2018 Dec 26;57(51):6997-7010. DOI:10.1021/acs.biochem.8b01096 |
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DC Chemicals
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Biorbyt Ltd.
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www.biorbyt.com |
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