瑞帕利辛L-賴氨酸鹽作用機(jī)制 - Medchemexpress - MCE中國

1、Product Data SheetReparixin L-lysine saltCat. No.: HY-15252CAS No.: 266359-93-7分式: CHNOS分量: 429.57作靶點(diǎn): CXCR作通路: GPCR/G Protein; Immunology/Inflammation儲存式: Powder -20C 3 years4C 2 yearsIn solvent -80C 6 months-20C 1 month溶解性數(shù)據(jù)體外實(shí)驗(yàn) H2O : 100 mg/mL (232.79 mM; Need ultrasonic)DMSO : 100 mg/mL (232.79

2、mM; Need ultrasonic)SolventMass1 mg 5 mg 10 mgConcentration制備儲備液1 mM 2.3279 mL 11.6395 mL 23.2791 mL5 mM 0.4656 mL 2.3279 mL 4.6558 mL10 mM 0.2328 mL 1.1640 mL 2.3279 mL請根據(jù)產(chǎn)品在不同溶劑中的溶解度選擇合適的溶劑配制儲備液；旦配成溶液，請分裝保存，避免反復(fù)凍融造成的產(chǎn)品失效。儲備液的保存式和期限：-80C, 6 months; -20C, 1 month。-80C 儲存時(shí)，請?jiān)?6 個(gè)內(nèi)使，-20C 儲存時(shí)，請?jiān)?1 個(gè)內(nèi)使。

3、體內(nèi)實(shí)驗(yàn)請根據(jù)您的實(shí)驗(yàn)動(dòng)物和給藥式選擇適當(dāng)?shù)娜芙獍?。以下溶解案都請先按?In Vitro 式配制澄清的儲備液，再依次添加助溶劑：為保證實(shí)驗(yàn)結(jié)果的可靠性，澄 的儲備液可以根據(jù)儲存條件，適當(dāng)保存；體內(nèi)實(shí)驗(yàn)的作液，建議您現(xiàn)現(xiàn)配，當(dāng)天使； 以下溶劑前顯的百分 指該溶劑在您配制終溶液中的體積占；如在配制過程中出現(xiàn)沉淀、析出現(xiàn)象，可以通過加熱和/或超聲的式助溶1. 請依序添加每種溶劑： 10% DMSO 40% PEG300 5% Tween-80 45% salineSolubility: 2.5 mg/mL (5.82 mM); Clear solution此案可獲得 2.5 mg/mL (5.82

4、 mM，飽和度未知) 的澄清溶液。以 1 mL 作液為例，取 100 L 25.0 mg/mL 的澄 DMSO 儲備液加到 400 L PEG300 中，混合均勻；向上述體系中加50 L Tween-80，混合均勻；然后繼續(xù)加 450 L 理鹽定容 1 mL。2. 請依序添加每種溶劑： 10% DMSO 90% (20% SBE-CD in saline)Solubility: 2.5 mg/mL (5.82 mM); Clear solutionPage 1 of 2 www.MedChemE此案可獲得 2.5 mg/mL (5.82 mM，飽和度未知) 的澄清溶液。以 1 mL 作液為例，

5、取 100 L 25.0 mg/mL 的澄 DMSO 儲備液加到 900 L 20% 的 SBE-CD 理鹽溶液中，混合均勻。3. 請依序添加每種溶劑： 10% DMSO 90% corn oilSolubility: 2.5 mg/mL (5.82 mM); Clear solution此案可獲得 2.5 mg/mL (5.82 mM，飽和度未知) 的澄 溶液，此案不適于實(shí)驗(yàn)周 期在半個(gè)以上的實(shí)驗(yàn)。以 1 mL 作液為例，取 100 L 25.0 mg/mL 的澄 DMSO 儲備液加到 900 L 油中，混合均勻。BIOLOGICAL ACTIVITY物活性 Reparixin L-lysi

6、ne salt趨化因受體1/2 (CXCR1/2)活化 的變構(gòu)抑制劑。IC & Target CXCR1wt CXCR1Ile43Val CXCR1 CXCR25.6 nM (IC50, in L1.2 cells) 80 nM (IC50, in L1.2 cells) 1 nM (IC50, in cells) -100 nM (IC50, in cells)體外研究 Reparixin is a potent functional inhibitor of CXCL8-induced biological activities on human PMNs with a markedsel

7、ectivity (around 400-fold) for CXCR1, as shown in specific experiments on CXCR1/L1.2 and CXCR2/L1.2 transfectedcells and on human PMNs. The efficacy of Reparixin is significantly lower in L1.2 cells expressing Ile43Val CXCR1mutant (IC50 values of 5.6 nM and 80 nM for CXCR1 wt and CXCR1 Ile43Val, res

8、pectively)1. Reparixin is a non-competitive allosteric inhibitor of IL-8 receptors with a 400-fold higher efficacy in inhibiting CXCR1 activity thanCXCR22.體內(nèi)研究 The pharmacokinetics and metabolism of Reparixin are investigated in rats and dogs after intravenous administrationof 14C-Reparixin L-lysine

9、 salt. Plasma protein binding of Reparixin is 99% in the laboratory animals and humans upto 50 g/mL, but lower at higher concentrations. Although radioactivity is rapidly distributed into rat tissues, Vss is low(about 0.15 L/kg) in both rat and dog. Nevertheless, Reparixin is more rapidly eliminated

10、 in rats (t1/20.5 h) than indogs (t1/210 h)3.PROTOCOLCell Assay 1 L1.2 Cell suspension (1.5-3106 cells/mL) is incubated at 37C for 15 min in the presence of vehicle or of Reparixin (1nM-1 M) and next seeded in triplicates in the upper compartment of the chemotactic chamber. Different agonistsare see

11、ded in the lower compartment of the chamber at the following concentrations: 1 nM CXCL8, 0.03 nM fMLP, 10nM CXCL1, 2.5 nM CCL2, 30 nM C5a. The chemotactic chamber is incubated at 37C in air with 5% CO2 for 45 min(human PMNs) or 2 h (monocytes). At the end of incubation, the filter is removed, fixed,

12、 and stained and five oilimmersion fields at high magnification (100) are counted for each migration well after sample coding. L1.2migration is evaluated using 5 m pore size Transwell filters1.MCE has not independently confirmed the accuracy of these methods. They are for reference only.Animal Rats

13、and Dogs3Administration 3 Male and female Sprague-Dawley CD (albino) rats and male Lister Hooded (partially pigmented) rats are used. Maleand female beagle Dogs (age about 15 months, bodyweight range 8.3-9.4 kg at the time of dosing) are used. Ratsand Dogs are dosed i.v. with repurified 14C-Reparixi

14、n free acid and an equivalent quantity of L-lysine suitablyradiodiluted with Reparixin L-lysine salt in a solution of sterile isotonic (0.9%, w/v) saline. Rats are dosed with asolution of total drug concentration 9 mg/mL at a dose volume of 5 mL/kg (30 mg free Reparixin /kg) by bolusinjection into a

15、 caudal vein. Dogs are dosed with a solution of total drug concentration 100 mg/mL at a dose volumeof 0.5 mL/kg (33 mg free Reparixin/kg) by bolus injection into a superficial forelimb vein.Page 2 of 3 www.MedChemEMCE has not independently confirmed the accuracy of these methods. They are for refere

16、nce only.戶使本產(chǎn)品發(fā)表的科研獻(xiàn) Ann Rheum Dis. 2016 Apr;75(4):730-8. Ann Rheum Dis. 2016 Apr;75(4):721-9. J Allergy Clin Immunol. 2018 Jun;141(6):2286-2289.e5. Sci Adv. 2019 May 8;5(5):eaav7384. Nat Commun. 2017 May 26;8:15584.See more customer validations on HYPERLINK www.MedChemE www.MedChemEREFERENCES1. Mor

17、iconi A, et al. Design of noncompetitive interleukin-8 inhibitors acting on CXCR1 and CXCR2. J Med Chem. 2007 Aug 23;50(17):3984-4002.2. Bertini R, et al. Receptor binding mode and pharmacological characterization of a potent and selective dual CXCR1/CXCR2non-competitive allostericinhibitor. Br J Ph

18、armacol. 2012 Jan;165(2):436-54.3. Midgley I, et al. Species differences in the pharmacokinetics and metabolism of reparixin in rat and dog. Xenobiotica. 2006 May;36(5):419-404. Catrina, Anca, et al. METHODS AND COMPOUNDS FOR THE TREATMENT OF BONE LOSS AND/OR PAIN. US 20170105971 A1.5. Bertini R, et al. Noncompetitive allosteric inhibitors of the inflammatory chemokine receptors CXCR1 and CXCR2: prevention of reperfusion inju