BX471-ZK-811752-DataSheet-生命科學(xué)試劑-MedChemExpress

1、Hotline: 400-820-3792Inhibitors Agonists Screening Librarieswww.MedChemEBX471Cat. No.: HY-12080CAS No.: 217645-70-0Synonyms: ZK-811752分式: CHClFNO分量: 434.89作靶點: CCR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)體外實驗 DMSO : 51 mg/

2、mL (117.27 mM)* means soluble, but saturation unknown.Mass Solvent1 mg 5 mg 10 mg Concentration制備儲備液1 mM 2.2994 mL 11.4972 mL 22.9943 mL5 mM 0.4599 mL 2.2994 mL 4.5989 mL10 mM 0.2299 mL 1.1497 mL 2.2994 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，并請注意儲備液的保存式和期限。體內(nèi)實驗請根據(jù)您的實驗動物和給藥式選擇適當(dāng)?shù)娜芙獍福渲魄罢埾扰渲瞥吻宓膬湟?，再依次添加助溶?為保

3、證實驗結(jié)果的可靠性，體內(nèi)實驗的作液，建議您現(xiàn)現(xiàn)配，當(dāng)天使；澄清的儲備液可以根據(jù)儲存條件，適當(dāng)保存；以下溶劑前的百分 指該溶劑在您配制終溶液中的體積占)：1. 請依序添加每種溶劑： 10% DMSO 40% PEG300 5% Tween-80 45% salineSolubility: 2.5 mg/mL (5.75 mM); Clear solution2. 請依序添加每種溶劑： 10% DMSO 90% (20% SBE-CD in saline)Solubility: 2.5 mg/mL (5.75 mM); Clear solution1/3 Master of Small Molec

4、ules 您邊的抑制劑師www.MedChemE3. 請依序添加每種溶劑： 10% DMSO 90% corn oilSolubility: 2.5 mg/mL (5.75 mM); Clear solutionBIOLOGICAL ACTIVITY物活性 BX471 (ZK-811752)以種服有效的，選擇性，多肽的 CCR1 拮抗劑，Ki 值為 1 nM，對其選擇性是對CCR2，CCR5 和 CXCR4 的 250 倍。IC50 & Target MIP-1-CCR1 RANTES-CCR1 MCP-3-CCR11 nM (Ki) 2.8 nM (Ki) 5.5 nM (Ki)體外研究 B

5、X471 is a potent functional antagonist based on its ability to inhibit a number of CCR1-mediated effectsincluding Ca2+ mobilization, increase in extracellular acidification rate, CD11b expression, and leukocytemigration. BX471 demonstrats a greater than 10,000-fold selectivity for CCR1 compared with

6、 28 G-protein-coupled receptors 1. BX471 is also able to displace 125I-MIP-1/CCL3 binding to mouse CCR1 in aconcentration-dependent manner with a Ki of 21546 nM. Increasing concentrations of BX471 inhibits theCa2+ transients induced by MIP-1/CCL3 in both human and mouse CCR1 with IC50 of 5.81 nM and

7、 1987nM, respectively 2. BX471 (0.1-10 M) shows a dose-dependent inhibition of RANTES-mediated and shear-resistant adhesion on IL-1-activated microvascular endothelium in shear flow in isolated blood monocytes.BX471 also inhibits the RANTES-mediated adhesion of T lymphocytes to activated endothelium

8、 4.體內(nèi)研究 BX471 (4 mg/kg, p.o. or i.v.) is orally active with a bioavailability of 60% in dogs. Furthermore, BX471effectively reduces disease in a rat experimental allergic encephalomyelitis model of multiple sclerosis 1.BX471 (20 mg/kg, s.c.) reaches peak plasma levels of 9 M by around 30 minutes, an

9、d this rapidly declinesto approximately 0.4 M after 2 hours. From 4 to 8 hours the drug plasma levels drops to 0.1 M or lower.Mice treated with 20 mg/kg of BX471 for 10 days shows a reduction of interstitial CD45 positive leukocytes ofapproximately 55%. BX471 has a borderline significant effect on t

10、he number of CCR5-positive CD8 cells inthe peripheral blood. BX471 reduces the amount of FSP1-positive cells by 65% in UUO kidneys as comparedwith vehicle control 2. Pretreatment witih BX471 reduces macrophage and neutrophil accumulation inkidney after ischemia-reperfusion injury 3.PROTOCOLAnimal Fa

11、sted male beagle dogs (n=3 per treatment group) are given BX471 either by oral gavage or by intravenousAdministration 1 injection via the cephalic vein at a dose of 4 mg/kg. The compound is dissolved in a vehicle of 40% aqueouscyclodextrin. Serial blood samples are collected utilizing an in-dwelling

12、 catheter in the jugular vein at theindicated time points up to 6 h post-dosing. EDTA is used as an anticoagulant. The samples are centrifuged(1000 g for 10 min at 4C), and plasma is stored frozen until analyzed for drug levels by HPLC-MS(electrospray mode operated under a positive ion mode). Plasma

13、 samples are thawed and denatured by theaddition of four parts of ice-cold methanol containing a fixed amount of an internal standard to one part ofplasma. The resulting protein precipitate is removed by centrifugation at 5000 g, and the supernatants areanalyzed directly. Concurrently plasma calibra

14、tion standards of BX471 are prepared over the range of2/3 Master of Small Molecules 您邊的抑制劑師www.MedChemEquantification, processed, and analyzed under identical conditions. A FISONS, VG Platform singlequadrupole instrument is used in these analyses with an electrospray inlet operated at 3.57 kV.Chroma

15、tographic separation is accomplished using a YMC AQ octadecyl silane reversed phase column(4.6250 mm) following a short isocratic elution method (35% methanol, 65% water containing 0.1%trifluoroacetic acid). The total column flow (1 mL/min) is split post-column to infuse 50 L/min into the massspectr

16、ometer. The chromatograms are collected over a total run time of 7.5 min/sample following a 50-Linjection on the column. The ions are collected in a single ion positive ionization mode. A calibration curve forquantification is generated by plotting ion current ratios between the internal standard pe

17、ak and the analyte inthe plasma standards over the quantification range. Calculations of percent oral availability is deduced fromthe area under curve measurements. Pharmacokinetic parameters are calculated using WinNonLin version3.0.MCE has not independently confirmed the accuracy of these methods.

18、 They are for reference only.戶使本產(chǎn)品發(fā)表的科研獻(xiàn) Cell Res. 2018 Mar;28(3):323-335. Immunol Lett. 2018 Oct 12;204:29-37.See more customer validations on HYPERLINK / www.MedChemEREFERENCES1. Liang M, et al. Identification and characterization of a potent, selective, and orally active antagonist of the CC chemokine receptor-1. JBiol Chem. 2000 Jun 23;275(25):19000-8.2. Anders HJ, et al. A chemokine receptor CCR-1 antagonist reduces renal fibrosis afte