AMD-070 - CAS 558447-26-0
Catalog number: 558447-26-0
Category: Inhibitor
Please be kindly noted products are not for therapeutic use. We do not sell to patients.
Molecular Formula:
C21H27N5
Molecular Weight:
349.47
COA:
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Targets:
CXCR
Description:
Potent and selective antagonist of CXCR4 (with an IC50 value of 13 nM in a CXCR4 125I-SDF inhibition binding assay)
Brife Description:
Potent and selective antagonist of CXCR4 (with an IC50 value of 13 nM in a CXCR4 125I-SDF inhibition binding assay)
Appearance:
White to gray solid
Synonyms:
(S)-N1-((1H-benzo[d]imidazol-2-yl)methyl)-N1-(5,6,7,8-tetrahydroquinolin-8-yl)butane-1,4-diamine; AMD11070; AMD-11070; AMD 11070; AMD-070; AMD 070; AMD070
Solubility:
10 mM in DMSO
Storage:
Please store the product under the recommended conditions in the Certificate of Analysis.
MSDS:
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Quality Standard:
In-house
Quantity:
Grams-Kilos
Melting Point:
108-110 ºC
InChIKey:
WVLHHLRVNDMIAR-IBGZPJMESA-N
InChI:
1S/C21H27N5/c22-12-3-4-14-26(15-20-24-17-9-1-2-10-18(17)25-20)19-11-5-7-16-8-6-13-23-21(16)19/h1-2,6,8-10,13,19H,3-5,7,11-12,14-15,22H2,(H,24,25)/t19-/m0/s1
Canonical SMILES:
NCCCCN(CC1=NC2=CC=CC=C2N1)[C@H]3CCCC4=C3N=CC=C4
1.Combination of drug therapy in acute lymphoblastic leukemia with a CXCR4 antagonist.
Parameswaran R1, Yu M, Lim M, Groffen J, Heisterkamp N. Leukemia. 2011 Aug;25(8):1314-23. doi: 10.1038/leu.2011.76. Epub 2011 Apr 12.
The bone marrow (BM) stromal niche can protect acute lymphoblastic leukemia (ALL) cells against the cytotoxicity of chemotherapeutic agents and is a possible source of relapse. The stromal-derived factor-1 (SDF-1)/CXCR4 axis is a major determinant in the crosstalk between leukemic cells and BM stroma. In this study, we investigated the use of AMD11070, an orally available, small-molecule antagonist of CXCR4, as an ALL-sensitizing agent. This compound effectively blocked stromal-induced migration of human ALL cells in culture and disrupted pre-established adhesion to stroma. To examine how to optimally use this compound in vivo, several combinations with cytotoxic drugs were tested in a stromal co-culture system. The best treatment regimen was then tested in vivo. Mice transplanted with murine Bcr/Abl ALL cells survived significantly longer when treated with a combination of nilotinib and AMD11070. Similarly, immunocompromised mice transplanted with human ALL cells and treated with vincristine and AMD11070 had few circulating leukemic cells, normal spleens and reduced human CD19+ cells in the BM at the termination of the experiment.
2.Discovery of novel small molecule orally bioavailable C-X-C chemokine receptor 4 antagonists that are potent inhibitors of T-tropic (X4) HIV-1 replication.
Skerlj RT1, Bridger GJ, Kaller A, McEachern EJ, Crawford JB, Zhou Y, Atsma B, Langille J, Nan S, Veale D, Wilson T, Harwig C, Hatse S, Princen K, De Clercq E, Schols D. J Med Chem. 2010 Apr 22;53(8):3376-88. doi: 10.1021/jm100073m.
The redesign of azamacrocyclic CXCR4 chemokine receptor antagonists resulted in the discovery of novel, small molecule, orally bioavailable compounds that retained T-tropic (CXCR4 using, X4) anti-HIV-1 activity. A structure-activity relationship (SAR) was determined on the basis of the inhibition of replication of X4 HIV-1 NL4.3 in MT-4 cells. As a result of lead optimization, we identified (S)-N'-((1H-benzo[d]imidazol-2-yl)methyl)-N'-(5,6,7,8-tetrahydroquinolin-8-yl)butane-1,4-diamine (AMD070) 2 as a potent and selective antagonist of CXCR4 with an IC(50) value of 13 nM in a CXCR4 125I-SDF inhibition binding assay. Compound 2 inhibited the replication of T-tropic HIV-1 (NL4.3 strain) in MT-4 cells and PBMCs with an IC(50) of 2 and 26 nM, respectively, while remaining noncytotoxic to cells at concentrations exceeding 23 microM. The pharmacokinetics of 2 was evaluated in rat and dog, and good oral bioavailability was observed in both species.
3.Ligand-guided optimization of CXCR4 homology models for virtual screening using a multiple chemotype approach.
Neves MA1, Simões S, Sá e Melo ML. J Comput Aided Mol Des. 2010 Dec;24(12):1023-33. doi: 10.1007/s10822-010-9393-x. Epub 2010 Oct 20.
CXCR4 is a G-protein coupled receptor for CXCL12 that plays an important role in human immunodeficiency virus infection, cancer growth and metastasization, immune cell trafficking and WHIM syndrome. In the absence of an X-ray crystal structure, theoretical modeling of the CXCR4 receptor remains an important tool for structure-function analysis and to guide the discovery of new antagonists with potential clinical use. In this study, the combination of experimental data and molecular modeling approaches allowed the development of optimized ligand-receptor models useful for elucidation of the molecular determinants of small molecule binding and functional antagonism. The ligand-guided homology modeling approach used in this study explicitly re-shaped the CXCR4 binding pocket in order to improve discrimination between known CXCR4 antagonists and random decoys. Refinement based on multiple test-sets with small compounds from single chemotypes provided the best early enrichment performance.
4.Hologram quantitative structure activity relationship, docking, and molecular dynamics studies of inhibitors for CXCR4.
Zhang C1, Du C, Feng Z, Zhu J, Li Y. Chem Biol Drug Des. 2015 Feb;85(2):119-36. doi: 10.1111/cbdd.12377. Epub 2014 Jul 10.
CXCR4 plays a crucial role as a co-receptor with CCR5 for HIV-1 anchoring to mammalian cell membrane and is implicated in cancer metastasis and inflammation. In the current work, we study the relationship of structure and activity of AMD11070 derivatives and other inhibitors of CXCR4 using HQSAR, docking and molecular dynamics (MD) simulations. We obtain an HQSAR model (q(2) = 0.779), and the HQSAR result illustrates that AMD11070 shows a high antiretroviral activity. As HQSAR only provides 2D information, we perform docking and MD to study the interaction of It1t, AMD3100, and AMD3465 with CXCR4. Our results illustrate that the binding are affected by two crucial residues Asp97 and Glu288. The butyl amine moiety of AMD11070 contributes to its high antiretroviral activity. Without a butyl amine moiety, (2,7a-Dihydro-1H-benzoimidazol-2-ylmethyl)-methyl-(5,6,7,8-tetrahydro-quinolin-8-yl)-amine (compound 5a) shows low antiretroviral activity.
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CAS 558447-26-0 AMD-070

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