|Numéro de catalogue: GC31744|
GSK2239633A est un antagoniste du récepteur CC-chimiokine 4 (CCR4), qui inhibe la liaison du [125I]-TARC au CCR4 humain avec une pIC50 de 7,96±0,11.
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Blood is taken from normal volunteers who have taken no medication within the previous 10 days and chemokine-induced increases in the filamentous (F)-actin content of CD4+ CCR4+ T cells are measured. Briefly, the peripheral blood mononuclear cells (PBMC) are isolated and stained with fluorescein isothiocyanate-conjugated anti-human CD4 and phycoerythrin-conjugated anti-CCR4 antibodies. The cells are then incubated with GSK2239633A (1 μM) or vehicle (0.1% DMSO) for 30 min at 37°C before stimulation with agonist for 15 sec. The assay is terminated by addition of 3% formaldehyde. The fixed cells are stained with Alexa fluor-647 phalloidin and the mean fluorescence intensity of 1000 CD4+ CCR4+ cells per sample is determined. This is expressed as a fraction of the mean intensity of the CD4+ CCR4- cells in the same sample.
Rats and DogsPharmacokinetics are determined in male Wistar Han rats (277-305 g) or male Sprague Dawley (crl:CD(SD)) rats 277-305 g) and male Beagle dogs (14-16 kg; aged approximately 3-4 years) following single oral and intravenous administration to aid prediction of the likely human pharmacokinetics using precedented physiological scaling techniques. In the rat, compounds (e.g., GSK2239633A) are dosed intravenously and orally to 2 rats per compound per route. Nominal doses of 1 mg/kg are used for intravenous (iv) and oral (po) administration and studies are conducted following routine animal husbandry methods. Rats are housed in standard holding cages and maintained in a controlled environment with free access to food and water. Serial blood samples are collected via a temporary cannula inserted into the tail vein of all animals. For the intravenously dosed animals the cannula is inserted into a vein discrete from that used for dosing. The dogs are kept in slings for no longer than 2 h following the end of dosing on each phase of the study. Compounds (e.g., GSK2239633A) are dosed intravenously (bolus, 0.5 mg/kg) using an angiocath and orally (gavage; 1 mg/kg) to two male Beagle dogs per compound in a cross over design. Serial blood samples are collected from the cephalic vein via an angiocath for the first 2 h post dose and via direct venipuncture for the remainder of the study.
. Cahn A, et al. Safety, tolerability, pharmacokinetics and pharmacodynamics of GSK2239633, a CC-chemokine receptor 4 antagonist, in healthy male subjects: results from an open-label and from a randomised study. BMC Pharmacol Toxicol. 2013 Feb 28;14:14.
GSK2239633A is a CC-chemokine receptor 4 (CCR4) antagonist, which inhibits the binding of [125I]-TARC to human CCR4 with a pIC50 of 7.96 ± 0.11.
The GSK2239633A is an allosteric antagonist of human CCR4. GSK2239633A inhibits the binding of [125I]-TARC to human CCR4 with a pIC50 of 7.96±0.11 and also inhibits thymus- and activation-regulated chemokine-induced (TARC)-induced increases in the F-actin content of isolated human CD4+ CCR4+ T-cells with a pA2 of 7.11±0.29. The effect of GSK2239633A (Compound 3) on CCL17-induced increases in the F-actin content of human CD4+ CCR4+ T cells is measured. The pEC50 value is 8.79±0.22.
Following intravenous dosing, plasma GSK2239633A displays rapid, bi-phasic distribution and slow terminal elimination (t1/2: 13.5 hours), suggesting that GSK2239633A is a low to moderate clearance drug. Following oral dosing, blood levels of GSK2239633A reach Cmax rapidly (median tmax: 1.0-1.5 hours). Estimated GSK2239633A bioavailability is low with a maximum value determined of only 16%. GSK2239633A (Compound 9) demonstrates good pharmacokinetic data in preclinical animal studies (bioavailability in rats and beagle dogs 85% and 97% respectively).
. Cahn A, et al. Safety, tolerability, pharmacokinetics and pharmacodynamics of GSK2239633, a CC-chemokine receptor 4 antagonist, in healthy male subjects: results from an open-label and from a randomised study. BMC Pharmacol Toxicol. 2013 Feb 28;14:14. . Slack RJ, et al. Antagonism of human CC-chemokine receptor 4 can be achieved through three distinct binding sites on the receptor. Pharmacol Res Perspect. 2013 Dec;1(2):e00019. . Miah AH, et al. Identification of pyrazolopyrimidine arylsulfonamides as CC-chemokine receptor 4 (CCR4) antagonists. Bioorg Med Chem. 2017 Oct 15;25(20):5327-5340.
|Solubilité||DMSO: ≥ 250 mg/mL (455.32 mM)||Storage||Store at -20°C|
|Conseils généraux||Afin d'obtenir une solubilité plus élevée, veuillez chauffer le tube à 37 °C et le secouer dans le bain à ultrasons pendant un certain temps. La solution mère peut être conservée à une température inférieure à -20 °C pendant plusieurs mois.|
|Condition d'expédition||Solution d'échantillon d'évaluation : livré avec la glace bleue
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Synthesis and structure-activity relationships of indazole arylsulfonamides as allosteric CC-chemokine receptor 4 (CCR4) antagonists
A series of indazole arylsulfonamides were synthesized and examined as human CCR4 antagonists. Methoxy- or hydroxyl-containing groups were the more potent indazole C4 substituents. Only small groups were tolerated at C5, C6, or C7, with the C6 analogues being preferred. The most potent N3-substituent was 5-chlorothiophene-2-sulfonamide. N1 meta-substituted benzyl groups possessing an α-amino-3-[(methylamino)acyl]-group were the most potent N1-substituents. Strongly basic amino groups had low oral absorption in vivo. Less basic analogues, such as morpholines, had good oral absorption; however, they also had high clearance. The most potent compound with high absorption in two species was analogue 6 (GSK2239633A), which was selected for further development. Aryl sulfonamide antagonists bind to CCR4 at an intracellular allosteric site denoted site II. X-ray diffraction studies on two indazole sulfonamide fragments suggested the presence of an important intramolecular interaction in the active conformation.
Safety, tolerability, pharmacokinetics and pharmacodynamics of GSK2239633, a CC-chemokine receptor 4 antagonist, in healthy male subjects: results from an open-label and from a randomised study
Background: The CC-chemokine receptor 4 (CCR4) is thought potentially to play a critical role in asthma pathogenesis due to its ability to recruit type 2 T-helper lymphocytes to the inflamed airways. Therefore, CCR4 provides an excellent target for anti-inflammatory therapy.
Methods: The safety, tolerability, pharmacokinetics and pharmacodynamics of the CCR4 antagonist GSK2239633, N-(3-((3-(5-chlorothiophene-2-sulfonamido)-4-methoxy-1H-indazol-1-yl)methyl)benzyl)-2-hydroxy-2-methylpropanamide, were examined in healthy males. Two studies were performed: 1) an open-label, study in which six subjects received a single intravenous infusion of [14C]-GSK2239633 100 μg (10 kBq) (NCT01086462), and 2) a randomised, double-blind, placebo-controlled, cross-over, ascending dose study in which 24 subjects received single oral doses of GSK2239633 150-1500 mg (NCT01371812).
Results: Following intravenous dosing, plasma GSK2239633 displayed rapid, bi-phasic distribution and slow terminal elimination (t?: 13.5 hours), suggesting that GSK2239633 was a low to moderate clearance drug. Following oral dosing, blood levels of GSK2239633 reached Cmax rapidly (median tmax: 1.0-1.5 hours). Estimated GSK2239633 bioavailability was low with a maximum value determined of only 16%. Food increased GSK2239633 systemic exposure (as assessed by AUC and Cmax). Increases in AUC and Cmax were less than dose proportional. Adverse events were reported by three subjects (50%) following intravenous administration, and by 19 subjects (79%) following oral administration; most (46/47; 98%) events were mild/moderate in intensity. GSK2239633 1500 mg inhibited thymus- and activation-regulated chemokine-induced (TARC) actin polymerisation reaching a mean CCR4 occupancy of 74%.
Conclusion: In conclusion, GSK2239633 was well-tolerated and capable of inhibiting TARC from activating the CCR4 receptor.
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