BX-471
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MedKoo CAT#: 510311

CAS#: 217645-70-0 (free base)

Description: BX-471, also known as ZK-811752, is a potent, selective non-peptide CCR1 antagonist (Ki = 1 nM for human CCR1). BX-471 exhibits 250-fold selectivity for CCR1 over CCR2, CCR5 and CXCR4. BX-471 was developed Berlex and its parent company, Schering AG. BX-471 is the lead in a series of non-peptide chemokine receptor 1 (CCR1) antagonists, for the potential treatment of autoimmune diseases, in particular multiple sclerosis (MS). In March 2000, BX-471 was undergoing phase I trials for the potential treatment of autoimmune diseases.


Chemical Structure

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BX-471
CAS# 217645-70-0 (free base)

Theoretical Analysis

MedKoo Cat#: 510311
Name: BX-471
CAS#: 217645-70-0 (free base)
Chemical Formula: C21H24ClFN4O3
Exact Mass: 434.1521
Molecular Weight: 434.89
Elemental Analysis: C, 58.00; H, 5.56; Cl, 8.15; F, 4.37; N, 12.88; O, 11.04

Price and Availability

Size Price Availability Quantity
10.0mg USD 150.0 Same day
25.0mg USD 250.0 Same day
50.0mg USD 450.0 Same day
100.0mg USD 650.0 Same day
200.0mg USD 950.0 Same day
500.0mg USD 1650.0 Same day
1.0g USD 2850.0 2 Weeks
2.0g USD 3950.0 2 Weeks
5.0g USD 5850.0 2 Weeks
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Related CAS #: 217645-70-0 (Free base)   288262-96-4 (HCl)  

Synonym: BX471; BX 471; BX-471; ZK811752; ZK 811752; ZK-811752.

IUPAC/Chemical Name: (R)-1-(5-chloro-2-(2-(4-(4-fluorobenzyl)-2-methylpiperazin-1-yl)-2-oxoethoxy)phenyl)urea

InChi Key: XQYASZNUFDVMFH-CQSZACIVSA-N

InChi Code: InChI=1S/C21H24ClFN4O3/c1-14-11-26(12-15-2-5-17(23)6-3-15)8-9-27(14)20(28)13-30-19-7-4-16(22)10-18(19)25-21(24)29/h2-7,10,14H,8-9,11-13H2,1H3,(H3,24,25,29)/t14-/m1/s1

SMILES Code: C[C@H]1N(C(COC2=CC=C(Cl)C=C2NC(N)=O)=O)CCN(CC3=CC=C(F)C=C3)C1

Appearance: Solid powder

Purity: >98% (or refer to the Certificate of Analysis)

Shipping Condition: Shipped under ambient temperature as non-hazardous chemical. This product is stable enough for a few weeks during ordinary shipping and time spent in Customs.

Storage Condition: Dry, dark and at 0 - 4 C for short term (days to weeks) or -20 C for long term (months to years).

Solubility: Soluble in DMSO, not in water

Shelf Life: >2 years if stored properly

Drug Formulation: This drug may be formulated in DMSO

Stock Solution Storage: 0 - 4 C for short term (days to weeks), or -20 C for long term (months).

HS Tariff Code: 2934.99.9001

Biological target: Bx471 is a selective non-peptide CCR1 antagonist with Ki of 1 nM and exhibits 250-fold selectivity for CCR1 over CCR2, CCR5 and CXCR4.
In vitro activity: Several well-studied CCR1 antagonists including AZD4818, BX471, CCX354, CP-481715, MLN-3897 and PS899877 were compared for their ability to inhibit binding of [125I]-CCL3 in vitro using membranes prepared from RPMI 8226 cells, a human multiple myeloma cell line that endogenously expresses CCR1. Using membranes from HEK_CCR1Gqi5 cells, it was confirmed that AZD-4818, BX471, CCX354, CP481715 and PS899877 are all potent inhibitors of [125I]-CCL3 binding Figure1;Table2). The compounds were then examined using membranes from RPMI 8226 cells (Figure 2, Table2;). Two compounds were equally potent with membranes from either cell line (BX471, PS899877). With HEK_CCR1 membranes it was found that MLN3879 > CCX354 ≥ AZD4818 > CP481715 = BX471 > PS899877 while with membranes from RPMI 8226 cells it was found that MLN3879 > BX471 > CP481715 ≥ PS899877 > AZD4818 > CCX354. Incubation of cells with AZD-4818, BX471, CCX354, MLN-3897 or PS899877 reduced CCL3-mediated receptor internalization and led to a dose-dependent recovery of surface CCR1 (Table 3; Figure2) although they all required higher concentrations than what was needed to block binding of I-CCL3. There appears to be biased antagonism with BX471, showing preference for reducing myeloma cell migration and β-arrestin translocation over CCR1 internalization or β-arrestin translocation. Reference: Br J Pharmacol. 2014 Nov; 171(22): 5127–5138. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4253460/
In vivo activity: In this study, the anti-inflammatory effect of BX471 was examined on ovalbumin (OVA)-induced AR mice model. The experiment utilized 30 female BALB/c mice, divided equally into three treatment groups: the normal group, the vehicle control group, and the BX471-treated group. The number of sneezes and the number of nasal-rubbing behaviors were different significantly between the normal group, the vehicle control group, and the BX471-treated group. As shown in Figure 2A, the number of sneezes significantly increased in the vehicle control group (20.9±1.5) compared with that of the normal group (1.1±0.7) during the 15 min period after the challenge (p<0.001). The number of sneezes in the BX471-treated group during the 15 min period after the challenge was 9.5±1.8, which was significantly attenuated compared with that of the vehicle control group (p<0.001) (Figure 2A); the number of nasalrubbing behaviors of the BX471-treated group was 107.6±14.0, which was significantly lower than that of the vehicle control group (p<0.05) (Figure 2B). The symptom scores indicate that BX471 treatment alleviated the symptoms of AR in mice. The BX471-treated group showed significantly lower levels of TNF-α in serum than the vehicle control group. Serum TNF-α levels were significantly (p<0.01) reduced in BX471 group compared with the vehicle control group (Figure 3B). The serum concentration of TNF-α in the vehicle control group was 27.54±4.39 pg/mL, whereas in the BX471-treated group that was 12.08±1.11 pg/mL (Figure 3B). Additionally, nasal expression levels of IL-4, IL-5, IL-13 were also significantly lower in BX471-treated group compared with the vehicle control group (Figure 5). Fold expression of IL-4 in the vehicle control group was 452.9±85.3 fold, whereas in the BX471treated group it was 38.5±15.7 fold (p<0.001). Overall, present study demonstrates that BX471 represents a promising therapeutic strategy against AR. Reference: J Inflamm Res. 2020; 13: 343–356. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7398876/

Solubility Data

Solvent Max Conc. mg/mL Max Conc. mM
Solubility
DMSO 56.0 128.77
Ethanol 18.0 41.39

Preparing Stock Solutions

The following data is based on the product molecular weight 434.89 Batch specific molecular weights may vary from batch to batch due to the degree of hydration, which will affect the solvent volumes required to prepare stock solutions.

Recalculate based on batch purity %
Concentration / Solvent Volume / Mass 1 mg 5 mg 10 mg
1 mM 1.15 mL 5.76 mL 11.51 mL
5 mM 0.23 mL 1.15 mL 2.3 mL
10 mM 0.12 mL 0.58 mL 1.15 mL
50 mM 0.02 mL 0.12 mL 0.23 mL
Formulation protocol: 1. Gilchrist A, Gauntner TD, Fazzini A, Alley KM, Pyen DS, Ahn J, Ha SJ, Willett A, Sansom SE, Yarfi JL, Bachovchin KA, Mazzoni MR, Merritt JR. Identifying bias in CCR1 antagonists using radiolabelled binding, receptor internalization, β-arrestin translocation and chemotaxis assays. Br J Pharmacol. 2014 Nov;171(22):5127-38. doi: 10.1111/bph.12835. PMID: 24990525; PMCID: PMC4253460. 2. Horuk R, Clayberger C, Krensky AM, Wang Z, Grone HJ, Weber C, Weber KS, Nelson PJ, May K, Rosser M, Dunning L, Liang M, Buckman B, Ghannam A, Ng HP, Islam I, Bauman JG, Wei GP, Monahan S, Xu W, Snider RM, Morrissey MM, Hesselgesser J, Perez HD. A non-peptide functional antagonist of the CCR1 chemokine receptor is effective in rat heart transplant rejection. J Biol Chem. 2001 Feb 9;276(6):4199-204. doi: 10.1074/jbc.M007457200. Epub 2000 Oct 27. PMID: 11054419. 3. Feng S, Ju L, Shao Z, Grzanna M, Jia L, Liu M. Therapeutic Effect of C-C Chemokine Receptor Type 1 (CCR1) Antagonist BX471 on Allergic Rhinitis. J Inflamm Res. 2020 Jul 21;13:343-356. doi: 10.2147/JIR.S254717. PMID: 32801828; PMCID: PMC7398876. 4. Vielhauer V, Berning E, Eis V, Kretzler M, Segerer S, Strutz F, Horuk R, Gröne HJ, Schlöndorff D, Anders HJ. CCR1 blockade reduces interstitial inflammation and fibrosis in mice with glomerulosclerosis and nephrotic syndrome. Kidney Int. 2004 Dec;66(6):2264-78. doi: 10.1111/j.1523-1755.2004.66038.x. PMID: 15569315.
In vitro protocol: 1. Gilchrist A, Gauntner TD, Fazzini A, Alley KM, Pyen DS, Ahn J, Ha SJ, Willett A, Sansom SE, Yarfi JL, Bachovchin KA, Mazzoni MR, Merritt JR. Identifying bias in CCR1 antagonists using radiolabelled binding, receptor internalization, β-arrestin translocation and chemotaxis assays. Br J Pharmacol. 2014 Nov;171(22):5127-38. doi: 10.1111/bph.12835. PMID: 24990525; PMCID: PMC4253460. 2. Horuk R, Clayberger C, Krensky AM, Wang Z, Grone HJ, Weber C, Weber KS, Nelson PJ, May K, Rosser M, Dunning L, Liang M, Buckman B, Ghannam A, Ng HP, Islam I, Bauman JG, Wei GP, Monahan S, Xu W, Snider RM, Morrissey MM, Hesselgesser J, Perez HD. A non-peptide functional antagonist of the CCR1 chemokine receptor is effective in rat heart transplant rejection. J Biol Chem. 2001 Feb 9;276(6):4199-204. doi: 10.1074/jbc.M007457200. Epub 2000 Oct 27. PMID: 11054419.
In vivo protocol: 1. Feng S, Ju L, Shao Z, Grzanna M, Jia L, Liu M. Therapeutic Effect of C-C Chemokine Receptor Type 1 (CCR1) Antagonist BX471 on Allergic Rhinitis. J Inflamm Res. 2020 Jul 21;13:343-356. doi: 10.2147/JIR.S254717. PMID: 32801828; PMCID: PMC7398876. 2. Vielhauer V, Berning E, Eis V, Kretzler M, Segerer S, Strutz F, Horuk R, Gröne HJ, Schlöndorff D, Anders HJ. CCR1 blockade reduces interstitial inflammation and fibrosis in mice with glomerulosclerosis and nephrotic syndrome. Kidney Int. 2004 Dec;66(6):2264-78. doi: 10.1111/j.1523-1755.2004.66038.x. PMID: 15569315.

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1: Vandemeulebroecke M, Lembcke J, Wiesinger H, Sittner W, Lindemann S. Assessment of QT(c)-prolonging potential of BX471 in healthy volunteers. A 'thorough QT study' following ICH E14 using various QT(c) correction methods. Br J Clin Pharmacol. 2009 Sep;68(3):435-46. doi: 10.1111/j.1365-2125.2009.03460.x. PubMed PMID: 19740402; PubMed Central PMCID: PMC2766484.

2: He M, Horuk R, Bhatia M. Treatment with BX471, a nonpeptide CCR1 antagonist, protects mice against acute pancreatitis-associated lung injury by modulating neutrophil recruitment. Pancreas. 2007 Mar;34(2):233-41. PubMed PMID: 17312463.

3: He M, Horuk R, Moochhala SM, Bhatia M. Treatment with BX471, a CC chemokine receptor 1 antagonist, attenuates systemic inflammatory response during sepsis. Am J Physiol Gastrointest Liver Physiol. 2007 Apr;292(4):G1173-80. Epub 2007 Jan 18. Erratum in: Am J Physiol Gastrointest Liver Physiol. 2012 Jan;302(1):G194. PubMed PMID: 17234893.

4: Horuk R. BX471: a CCR1 antagonist with anti-inflammatory activity in man. Mini Rev Med Chem. 2005 Sep;5(9):791-804. Review. PubMed PMID: 16178722.
 

BX-471

10.0mg / USD 150.0


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