AMD3465 hexahydrobromide - CAS 185991-07-5
Category: Inhibitor
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AMD3465 is a potent and highly selective monomacrocyclic CXCR4 antagonist (IC50= 0.75 nM). It potently inhibits HIV cell entry in vitro and causes leukocytosis and mobilizes haematopoietic stem cells in vivo. It dose dependently inhibits eosinophil recruitment during type-2 granuloma formation and interferes with primary and secondary T-cell activation events in lymphoid tissue.
Brife Description:
A potent and highly selective monomacrocyclic CXCR4 antagonist (IC50= 0.75 nM)
99.43 %
Related CAS:
185991-24-6 (free base)
Pale Yellow Solid
Soluble to 50 mM in water and to 25 mM in DMSO
Store in a cool and dry place (or refer to the Certificate of Analysis).
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1.Entry inhibitor-based microbicides are active in vitro against HIV-1 isolates from multiple genetic subtypes.
Ketas TJ;Schader SM;Zurita J;Teo E;Polonis V;Lu M;Klasse PJ;Moore JP Virology. 2007 Aug 1;364(2):431-40. Epub 2007 Apr 10.
Inhibitors of viral entry are under consideration as topical microbicides to prevent HIV-1 sexual transmission. Small molecules targeting HIV-1 gp120 (BMS-378806) or CCR5 (CMPD167), and a peptide fusion inhibitor (C52L), each blocks vaginal infection of macaques by a SHIV. A microbicide, however, must be active against multiple HIV-1 variants. We therefore tested BMS-C (a BMS-378806 derivative), CMPD167, C52L and the CXCR4 ligand AMD3465, alone and in combination, against 25 primary R5, 12 X4 and 7 R5X4 isolates from subtypes A-G. At high concentrations (0.1-1 microM), the replication of most R5 isolates in human donor lymphocytes was inhibited by >90%. At lower concentrations, double and triple combinations were more effective than individual inhibitors. Similar results were obtained with X4 viruses when AMD3465 was substituted for CMPD167. The R5X4 viruses were inhibited by combining AMD3465 with CMPD167, or by the coreceptor-independent compounds. Thus, combining entry inhibitors may improve microbicide effectiveness.
2.AMD3465, a monomacrocyclic CXCR4 antagonist and potent HIV entry inhibitor.
Hatse S;Princen K;De Clercq E;Rosenkilde MM;Schwartz TW;Hernandez-Abad PE;Skerlj RT;Bridger GJ;Schols D Biochem Pharmacol. 2005 Sep 1;70(5):752-61.
The chemokine receptors CCR5 and CXCR4 function as coreceptors for human immunodeficiency virus (HIV) and are attractive targets for the development of anti-HIV drugs. The most potent CXCR4 antagonists described until today are the bicyclams. The prototype compound, AMD3100, exhibits potent and selective anti-HIV activity against CXCR4-using (X4) viruses and showed antiviral efficacy in X4 HIV-1-infected persons in a phase II clinical trial. However, AMD3100 lacks oral bioavailability due to its high overall positive charge. Initial structure-activity relationship studies with bicyclam analogues suggested that the bis-macrocyclic structure was a prerequisite for anti-HIV activity. Now, we report that the N-pyridinylmethylene cyclam AMD3465, which lacks the structural constraints mentioned above, fully conserves all the biological properties of AMD3100. Like AMD3100, AMD3465 blocked the cell surface binding of both CXCL12 (the natural CXCR4 ligand), and the specific anti-CXCR4 monoclonal antibody 12G5. AMD3465 dose-dependently inhibited intracellular calcium signaling, chemotaxis, CXCR4 endocytosis and mitogen-activated protein kinase phosphorylation induced by CXCL12. Compared to the bicyclam AMD3100, AMD3465 was even 10-fold more effective as a CXCR4 antagonist, while showing no interaction whatsoever with CCR5.
3.An update in the development of HIV entry inhibitors.
Rusconi S;Scozzafava A;Mastrolorenzo A;Supuran CT Curr Top Med Chem. 2007;7(13):1273-89.
HIV entry and fusion are two steps in the viral life cycle that can be targeted by several classes of antiviral drugs. The discovery of chemokines focused the attention on cellular coreceptors used by the virus for entering within cells, and to the various steps of such processes which are subject to interactions with small molecules. Intense research led to a wide range of effective compounds that are able to inhibit these initial steps of viral replication. All steps in the process of HIV entry into the cell may be targeted by specific compounds that may be developed as novel types of antiretrovirals. Thus, several inhibitors of the gp120-CD4 interaction have been detected so far (zintevir, FP-21399 and BMS-378806 in clinical trials). Small molecule chemokine receptor antagonists acting as HIV entry inhibitors also were described in the last period, which interact both with the CXCR4 coreceptor (such as AMD3100; AMD3465; ALX40-4C; T22, T134 and T140), or which are antagonist of the CCR5 coreceptor (TAK-779, TAK-220, SCH-C, SCH-D, E913, AK-602 and NSC 651016 in clinical trials), together with new types of fusion inhibitors possessing the same mechanism of action as enfuvirtide (such as T1249).
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