155148-31-5

Plerixafor (155148-31-5) is a highly selective CXCR4 antagonist (IC50 = 20-130 nM).1,2 Originally investigated as an HIV replication inhibitor.3 Plerixafor has been investigated for the treatment autoimmune diseases and various cancers.4 Clinically useful for the mobilization of hematopoietic stem cells in the treatment of blood cancers.

A specific CXCR4 antagonist.

Plerixafor 8HCl (AMD3100 8HCl) is the hydrochloride of Plerixafor, a chemokine receptor antagonist for CXCR4 and CXCL12-mediated chemotaxis with IC50 of 44 nM and 5.7 nM, respectively - See more at: http://www.selleckchem.com/products/plerixafor-8hcl-db06

Highly selective CXCR4 chemokine receptor antagonist (IC 50 values are 0.02 - 0.13 and > 25 μ M for CXCR4 and all other chemokine receptors respectively). Switches inflammatory responses from Th2 to Th1 type and reduces airway hyperresponsiveness in a mouse model of asthma. Potently inhibits HIV-1 and HIV-2 replication in vitro (EC 50 = 4 - 35 nM) and mobilizes hematopoietic stem cells in vivo .

Cell permeable: yes

Plerixafor hydrochloride, a chemokine CXCR4 (SDF-1) antagonist, was launched by Genzyme for the treatment of enhancing mobilization of hematopoietic stem cells for autologous transplantation in patients with lymphoma and enhancing mobilization of hematopoietic stem cells for transplantation in patients with multiple myeloma. Being a CXCR4 antagonist, a specific cellular chemokine receptor, plerixafor triggers the rapid movement of stem cells out of the bone marrow and into circulating blood where the stem cells can be collected for use in stem cell transplants. Regarding its use for cardiac applications, some clinical data suggests that the presence of stem cells circulating in the bloodstream or directly injected into the hearts of patients who have suffered a heart attack may result in improved cardiac function.

A concise one-pot synthesis was achieved by a rather novel nitrogen protecting strategy. Tetraazacyclotetradecane 88 was protected as its phosphorotriamide 89 by reaction with POCl3 and Et3N in hot DMF. Without isolation, compound 89 was bis-alkylated with dibromide 90 in the presence of sodium carbonate in refluxing DMF overnight to give bis-phosphoramide 91. The crude dimeric bis-phosphoramide was hydrolyzed with 3 M HCl to afford plerixafor hydrochloride (XV) in 62¨C68% yield.

This metal ion-chelating immunostimulant (FW = 502.80 g/mol; CAS 155148-31-5), also known by its code names AMD3100 and JM3100, its trade name Mozobil? as well as its systematic name 1,1’-[1,4- phenylenebis (methylene) ]bis-[1,4,8,11-tetraazacyclotetradecane], is an a-C- X-C chemokine receptor CXCR4 antagonist (or partial agonist) and an allosteric CXCR7 agonist (1-4). The active chemical form is likely to contain divalent zinc ion. (See also TC 14012) Likely Mode of Action: The CXCR4 a-chemokine is stimulated by Stromal cell-Derived Factor-1 (or SDF-1) that plays roles in hematopoietic stem cell homing to the bone marrow and in hematopoietic stem cell (HSC) quiescence. CXCR7) is a G- protein-coupled receptor (GPCR) that binds the chemokines CXCL12/SDF- 1 and CXCL11 and serves as a coreceptor for human immunodeficiency viruses. Plerixafor inhibits the replication of various HIV-1 and HIV-2 strains in various cell lines (EC50 = 1-10 ng/mL, or >100,000x lower than its cytotoxic concentration of 500 μg/mL). When combined with either 3'- azido-2',3' -dideoxythymidine or 2',3'-dideoxyinosine, JM3100 achieved a additive inhibition of HIV replication, and when repeatedly subcultivated in the presence of JM3100, with the virus remaining sensitive to the compound for at least 30 passages in culture. AMD3100 blocks HIV-1 entry and membrane fusion via the CXCR4 co-receptor, blocking the latter’s role as both a HIV-1 co-receptor and a CXC-chemokine receptor . Use as an Investigational Drug: Plerixafor’s discovery provided a new way to mobilize HSC for autologous transplantation. In 2008, plerixafor was approved by the FDA for the mobilization of hematopoietic stem cells. Plerixafor is also an investigational drug for the treatment of WHIM Syndrome (standing for Warts, Hypogammaglobulinemia, Infection & Myelokathexis Syndrome), a rare congenital immunodeficiency disorder characterized by chronic noncyclic neutropenia and arising from gain-of- function deletion mutations in CXCR4. In a Phase-I study, circulating leukocytes were durably increased throughout the trial in all patients, and this was associated with fewer infections and improvement in warts in combination with imiquimod; however immunoglobulin levels and specific vaccine responses were not fully restored. Metal Ion Binding: Plerixafor binds zinc, copper nickel, cobalt and2 +rhodium ions, and the biologically active form is the 1:2 Plerixafor-Zn ternary complex (FW = 627.53 g/mol). Other CXCR4 antagonists include: AMD070, T140, FC131, FC122, with several being evident metal ion-binding chelators. The diversity of their structures suggests the possibility that they may act as divalent metallophores, a unique class of organic molecules that facilitate metal ion transfer across membrane bilayers in a manner akin to the valinomycin- facilitated transport of potassium ion or by means of a vesicle pathway, such as receptor-mediated endocytosis.

-20°C (desiccate)

1) Donzella, et al. (1998), AMD3100, A Small Molecule Inhibitor of HIV-1 Entry via the CXCR4 Co-Receptor; Nat. Med. 4 72 2) Hatse et al. (2002), Chemokine Receptor Inhibition by AMD3100 Is Strictly Confined to CXCR4; FEBS Lett. 527 255 3) Bridger et al. (1995), Synthesis and Structure-Activity Relationships of Phenylenebis(methylene)-linked Bis-Tetraazamacrocycles That Inhibit HIV Replication. Effects of Macrocyclic Ring Size and Substituents on the aromatic Linker; J. Med. Chem. 38 366 4) Wang et al. (2020), CXCR4 antagonist AMD3100 (plerixafor): from an impurity to a therapeutic agent; Pharmacol. Res. 159 105010