N-Desethyl SunitinibVEGFR/PDGFRβ/KIT inhibitor CAS# 356068-97-8 |
- SU14813
Catalog No.:BCC1971
CAS No.:627908-92-3
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| Cas No. | 356068-97-8 | SDF | Download SDF |
| PubChem ID | 10292573 | Appearance | Powder |
| Formula | C20H23FN4O2 | M.Wt | 370.42 |
| Type of Compound | N/A | Storage | Desiccate at -20°C |
| Synonyms | SU-11662 | ||
| Solubility | DMSO : 50 mg/mL (134.98 mM; Need ultrasonic) | ||
| Chemical Name | N-[2-(ethylamino)ethyl]-5-[(Z)-(5-fluoro-2-oxo-1H-indol-3-ylidene)methyl]-2,4-dimethyl-1H-pyrrole-3-carboxamide | ||
| SMILES | CCNCCNC(=O)C1=C(NC(=C1C)C=C2C3=C(C=CC(=C3)F)NC2=O)C | ||
| Standard InChIKey | LIZNIAKSBJKPQC-GDNBJRDFSA-N | ||
| Standard InChI | InChI=1S/C20H23FN4O2/c1-4-22-7-8-23-20(27)18-11(2)17(24-12(18)3)10-15-14-9-13(21)5-6-16(14)25-19(15)26/h5-6,9-10,22,24H,4,7-8H2,1-3H3,(H,23,27)(H,25,26)/b15-10- | ||
| General tips | For obtaining a higher solubility , please warm the tube at 37 ℃ and shake it in the ultrasonic bath for a while.Stock solution can be stored below -20℃ for several months. We recommend that you prepare and use the solution on the same day. However, if the test schedule requires, the stock solutions can be prepared in advance, and the stock solution must be sealed and stored below -20℃. In general, the stock solution can be kept for several months. Before use, we recommend that you leave the vial at room temperature for at least an hour before opening it. |
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| About Packaging | 1. The packaging of the product may be reversed during transportation, cause the high purity compounds to adhere to the neck or cap of the vial.Take the vail out of its packaging and shake gently until the compounds fall to the bottom of the vial. 2. For liquid products, please centrifuge at 500xg to gather the liquid to the bottom of the vial. 3. Try to avoid loss or contamination during the experiment. |
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| Shipping Condition | Packaging according to customer requirements(5mg, 10mg, 20mg and more). Ship via FedEx, DHL, UPS, EMS or other couriers with RT, or blue ice upon request. | ||
| Description | N-Desethyl Sunitinib is a metabolite of sunitinib. Sunitinib is a potent, ATP-competitive VEGFR, PDGFRβ and KIT inhibitor with Ki values of 2, 9, 17, 8 and 4 nM for VEGFR -1, -2, -3, PDGFRβ and KIT, respectively.In Vitro:Sunitinib also potently inhibits Kit and FLT-3[1]. Sunitinib is a potent ATP-competitive inhibitor of VEGFR2 (Flk1) and PDGFRβ with Ki of 9 nM and 8 nM, respectively, displaying >10-fold higher selectivity for VEGFR2 and PDGFR than FGFR-1, EGFR, Cdk2, Met, IGFR-1, Abl, and src. In serum-starved NIH-3T3 cells expressing VEGFR2 or PDGFRβ, Sunitinib inhibits VEGF-dependent VEGFR2 phosphorylation and PDGF-dependent PDGFRβ phosphorylation with IC50 of 10 nM and 10 nM, respectively. Sunitinib inhibits VEGF-induced proliferation of serum-starved HUVECs with IC50 of 40 nM, and inhibits PDGF-induced proliferation of NIH-3T3 cells overexpressing PDGFRβ or PDGFRα with IC50 of 39 nM and 69 nM, respectively[2]. Sunitinib inhibits phosphorylation of wild-type FLT3, FLT3-ITD, and FLT3-Asp835 with IC50 of 250 nM, 50 nM, and 30 nM, respectively. Sunitinib inhibits the proliferation of MV4;11 and OC1-AML5 cells with IC50 of 8 nM and 14 nM, respectively, and induces apoptosis in a dose-dependent manner[3].In Vivo:Sunitinib (20-80 mg/kg/day) exhibits broad and potent dose-dependent anti-tumor activity against a variety of tumor xenograft models including HT-29, A431, Colo205, H-460, SF763T, C6, A375, or MDA-MB-435, consistent with the substantial and selective inhibition of VEGFR2 or PDGFR phosphorylation and signaling in vivo. Sunitinib (80 mg/kg/day) for 21 days leads to complete tumor regression in six of eight mice, without tumor re-growing during a 110-day observation period after the end of treatment. Second round of treatment with Sunitinib remains efficacious against tumors that are not fully regressed during the first round of treatment. Sunitinib treatment results in significant decrease in tumor MVD, with appr 40% reduction in SF763T glioma tumors. SU11248 treatment results in a complete inhibition of additional tumor growth of luciferase-expressing PC-3M xenografts, despite no reduction in tumor size[2]. Sunitinib treatment (20 mg/kg/day) dramatically suppresses the growth subcutaneous MV4;11 (FLT3-ITD) xenografts and prolongs survival in the FLT3-ITD bone marrow engraftment model[3]. References: | |||||
N-Desethyl Sunitinib Dilution Calculator
N-Desethyl Sunitinib Molarity Calculator
| 1 mg | 5 mg | 10 mg | 20 mg | 25 mg | |
| 1 mM | 2.6996 mL | 13.4982 mL | 26.9964 mL | 53.9928 mL | 67.491 mL |
| 5 mM | 0.5399 mL | 2.6996 mL | 5.3993 mL | 10.7986 mL | 13.4982 mL |
| 10 mM | 0.27 mL | 1.3498 mL | 2.6996 mL | 5.3993 mL | 6.7491 mL |
| 50 mM | 0.054 mL | 0.27 mL | 0.5399 mL | 1.0799 mL | 1.3498 mL |
| 100 mM | 0.027 mL | 0.135 mL | 0.27 mL | 0.5399 mL | 0.6749 mL |
| * Note: If you are in the process of experiment, it's necessary to make the dilution ratios of the samples. The dilution data above is only for reference. Normally, it's can get a better solubility within lower of Concentrations. | |||||
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Lu AE58054 hydrochloride is an in-vivo binding affinity and effect, in-vitro selectivity and potency of 5-HT(6)R antagonist with Ki value of 0.83 nM [1].
The serotonin6 receptor (5-HT6R) is one of 14 known 5-HTRs in the serotonin receptor family [1]. It plays an important role in cognitive impairments associated with Alzheimer's disease and schizophrenia [2].
In the 5-HT(6) GTP gamma S efficacy assay, Lu AE58054 showed potent inhibition of 5-HT-mediated activation. Apart from medium affinity to adrenergic alpha (1B)- and alpha(1A)-adrenoreceptors, Lu AE58054 shows >50-fold selectivity compared with more than 70 targets examined [1].
In rats model, Orally administered Lu AE58054 inhibited binding of the 5-HT6 antagonist Lu AE60157 with ED50 of 2.7 mg/kg. Administration of Lu AE58054 in a dose range (5–20 mg/kg) leading to above 65% 5-HT6R binding, which reversed cognitive impairment in rats treatment with phencyclidine. These results indicate that Lu AE58054 is a potent antagonist of 5-HT6Rs with good oral bioavailability in the rat model of cognitive impairment in schizophrenia [1].
References:
[1]. Arnt J, Bang-Andersen B, Grayson B, et al. Lu AE58054, a 5-HT6 antagonist, reverses cognitive impairment induced by subchronic phencyclidine in a novel object recognition test in rats. Int J Neuropsychopharmacol, 2010, 13(8): 1021-1033.
[2]. Witten L, Bang-Andersen B, Nielsen SM, et al. Molecular and Cellular Pharmacology.Characterization of [3H]Lu AE60157 ([3H]8-(4-methylpiperazin-1-yl)-3-phenylsulfonylquinoline) binding to 5-hydroxytryptamine6 (5-HT6) receptors in vivo. Eur J Pharmacol, 2012, 676(1-3): 6-11.
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P-glycoprotein (ABCB1) and breast cancer resistance protein (ABCG2) restrict brain accumulation of the active sunitinib metabolite N-desethyl sunitinib.[Pubmed:22238213]
J Pharmacol Exp Ther. 2012 Apr;341(1):164-73.
N-Desethyl Sunitinib is a major and pharmacologically active metabolite of the tyrosine kinase inhibitor and anticancer drug sunitinib. Because the combination of N-Desethyl Sunitinib and sunitinib represents total active drug exposure, we investigated the impact of several multidrug efflux transporters on plasma pharmacokinetics and brain accumulation of N-Desethyl Sunitinib after sunitinib administration to wild-type and transporter knockout mice. In vitro, N-Desethyl Sunitinib was a good transport substrate of human ABCB1 and ABCG2 and murine Abcg2, but not ABCC2 or Abcc2. At 5 muM, ABCB1 and ABCG2 contributed almost equally to N-Desethyl Sunitinib transport. In vivo, the systemic exposure of N-Desethyl Sunitinib after oral dosing of sunitinib malate (10 mg/kg) was unchanged when Abcb1 and/or Abcg2 were absent. However, brain accumulation of N-Desethyl Sunitinib was markedly increased (13.7-fold) in Abcb1a/1b(-/-)/Abcg2(-/-) mice, but not in Abcb1a/1b(-/-) or Abcg2(-/-) mice. In the absence of the ABCB1 and ABCG2 inhibitor elacridar, brain concentrations of N-Desethyl Sunitinib were detectable only in Abcb1a/1b(-/-)/Abcg2(-/-) mice after sunitinib administration. Combined elacridar plus N-Desethyl Sunitinib treatment increased N-Desethyl Sunitinib plasma and brain exposures, but not brain-to-plasma ratios in wild-type mice. In conclusion, brain accumulation of N-Desethyl Sunitinib is effectively restricted by both Abcb1 and Abcg2. The effect of elacridar treatment in improving brain accumulation of N-Desethyl Sunitinib in wild-type mice was limited compared with its effect on sunitinib brain accumulation.
Quantification of sunitinib and N-desethyl sunitinib in human EDTA plasma by liquid chromatography coupled with electrospray ionization tandem mass spectrometry: validation and application in routine therapeutic drug monitoring.[Pubmed:23503442]
Ther Drug Monit. 2013 Apr;35(2):168-76.
BACKGROUND: Given the low therapeutic index, the large interindividual variability in systemic exposure and the positive exposure-efficacy relationship of sunitinib, there is a rationale for therapeutic drug monitoring (TDM) of sunitinib. To support TDM, a method for determination of sunitinib and its active metabolite (N-Desethyl Sunitinib) has been developed and validated. METHODS: For determination of sunitinib and N-Desethyl Sunitinib in human EDTA plasma samples, high-performance liquid chromatography coupled to tandem mass spectrometry (HPLC-MS/MS) was used. Validation experiments according to Food and Drug Administration guidelines were performed. In addition, the results of 25 analytical runs with 58 patient samples using 8 calibrators and 3 levels of quality control (QC) samples per analysis were compared with the results of analyses using only 3 calibrators and 1 QC sample to accelerate sample turnaround time. The method comparison experiment was performed according to international guidelines. RESULTS: The HPLC-MS/MS method was validated over a linear range from 2.5 to 500 ng/mL using 50 muL plasma volumes, with good intra- and interassay accuracy and precision. In addition, the mean of the absolute differences between the compared methods was only -0.66 ng/mL (mean of relative differences, -0.85%), which is not a clinically relevant difference. CONCLUSIONS: This method has been applied successfully for routine TDM purposes for patients treated with sunitinib. Moreover, reliable results with a rapid turnaround time were obtained when performing a short analytical run containing only 3 calibrators and 1 QC sample.
Quantitation of unbound sunitinib and its metabolite N-desethyl sunitinib (SU12662) in human plasma by equilibrium dialysis and liquid chromatography-tandem mass spectrometry: application to a pharmacokinetic study.[Pubmed:22259028]
Biomed Chromatogr. 2012 Nov;26(11):1315-24.
A rapid, selective, and sensitive liquid chromatography-tandem mass spectrometry method was developed and validated for the simultaneous determination of unbound sunitinib and its active metabolite N-Desethyl Sunitinib in plasma. Plasma and post-dialysis buffer samples were extracted using a liquid-liquid extraction procedure with acetonitrile-n-butylchloride (1:4, v/v). Chromatographic separation was achieved on a Waters X-Terra(R) MS RP(18) column with a mobile phase consisting of acetonitrile and water (60:40, v/v) containing formic acid (0.1%, v/v) using an isocratic run, at a flow-rate of 0.2 mL/min. Analytes were detected by electrospray tandem mass spectrometry in the selective reaction monitoring mode. Linear calibration curves were generated over the ranges 0.1-100 and 0.02-5 ng/mL for sunitinib and 0.2-200 and 0.04-10 ng/mL for N-Desethyl Sunitinib in plasma and in phosphate-buffered solution, respectively. The values for both within-day and between-day precision and accuracy were well within the generally accepted criteria for analytical methods. The analytical range was sufficient to determine the unbound and total concentrations of both analytes. The method was applied for measurement unbound concentrations in addition to total concentrations of sunitinib and its metabolite in plasma of a cancer patient receiving 50 mg daily dose.
Determination of sunitinib and its active metabolite, N-desethyl sunitinib in mouse plasma and tissues by UPLC-MS/MS: assay development and application to pharmacokinetic and tissue distribution studies.[Pubmed:25294592]
Biomed Chromatogr. 2015 May;29(5):679-88.
A simple, sensitive and specific method using ultraperformance liquid chromatography/tandem mass spectrometry (UPLC-MS/MS) was developed to determine sunitinib and N-Desethyl Sunitinib in mouse plasma and tissues. The analytes were separated by an isocratic mobile phase consisting of acetonitrile and buffer solution (water with 0.1% formic acid and 5 m m ammonium acetate; 40: 60, v/v) running at a flow rate of 0.35 mL/min for 2 min. Quantification was performed using a mass spectrometer by multiple reaction monitoring in positive electrospray ionization mode. The transition was monitored at m/z 399 --> 283, m/z 371 --> 283 and m/z 327 --> 270 for sunitinib, N-Desethyl Sunitinib and internal standard, respectively. Calibration curves were linear over concentration ranges of 2-500, 0.5-50 and 1-250 ng/mL for plasma, heart and other biosamples. The method was successfully applied to animal experiments. The pharmacokinetic study indicated that sunitinib was eliminated quickly in mice with a half-life of 1.2 h; tissue distribution data showed more sunitinib and its metabolite in liver, spleen and lung, which provided reference for further study.
