Plerixafor
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Non-proprietary name | Plerixafor | ||||||||||||
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Molecular formula | C 28 H 54 N 8 | ||||||||||||
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Molar mass | 502.79 g · mol -1 | ||||||||||||
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As far as possible and customary, SI units are used. Unless otherwise noted, the data given apply to standard conditions . |
Plerixafor (also: AMD3100 and JM3100 ) is a drug from the group of bicycles marketed by the Genzyme company , which is used to release stem cells into the bloodstream and then perform autologous stem cell transplantation. Plerixafor is the first CXCR4 inhibitor to be approved by the US Food and Drug Administration (FDA), and it was approved for Europe since 2009.
history
Plerixafor was discovered by the Johnson Matthey Technology Center in the early 1990s for its anti- HIV effectiveness. After Johnson Matthey joined the newly founded AnorMED Inc. , Plerixafor initially sought to use it in HIV therapy. Plerixafor has been shown to be effective against X4-trope HIV-1 strains in clinical studies after parenteral administration. Due to the lack of oral bioavailability of the drug combined with the inevitable necessity of a less popular parenteral administration, the intended use as an HIV therapeutic agent was discarded due to poor market opportunities. Plerixafor was granted orphan drug status in 2003 . In December 2008, the Plerixafor preparation Mozobil ™ was approved by the American FDA, and in May 2009 the European Medicines Agency followed .
chemistry
properties
Plerixafor is a strongly basic chemical compound with eight protonatable nitrogen atoms . The cyclam groups of the Plerixafor are able to form stable complexes with divalent metal ions , in particular zinc , copper and nickel , and also with cobalt and rhodium . Under physiological conditions, Plerixafor is also present as a biologically active zinc complex. Plerixafor can thus be regarded as a prodrug of its zinc complex.
synthesis
The synthesis of Plerixafor is described as a multi-step process. Initially, three of the four nitrogen atoms of 1,4,8,11-tetraazacyclotetradecane are protected with tosyl groups . The resulting tristosyl-1,4,8,11-tetraazacyclotetradecane is reacted with p - xylene glycol or 1,4-bis (bromomethyl) benzene in the presence of potassium carbonate in acetonitrile . After the tosyl protective groups have been split off using hydrobromic acid , plerixafor can be isolated as octahydrobromide.
pharmacology
application areas
Plerixafor is approved in the US in combination with G-CSF to release stem cells from the bone marrow into the bloodstream for the purpose of stem cell isolation for stem cell transplantation in patients with multiple myeloma or non-Hodgkin lymphoma .
The Committee for Human Use (CHMP) of the European Medicines Agency (EMA) has end in March 2019 recommended a label extension for plerixafor (Mozobil, Genzyme): in future it should in combination with G-CSF for mobilization of hematopoietic stem cells in children with lymphoma or solid malignant tumors can be used pre-emptively or after insufficient collection of stem cells. So far, use has been limited to adult patients. (The European Commission usually complies with such a recommendation.)
In WHIM syndrome (wart hypogammaglobulinaemia-immunodeficiency-myelocathexis syndrome) there is a mutation of the CXRC4 receptor that leads to an increase in function and thus prevents the release of white blood cells from the bone marrow. In a study it could be shown that Plerixafor has a positive effect on the clinical picture. Outside of studies, there is no approval for the treatment of WHIM syndrome with Plerixafor in either the USA or Germany (as of February 27, 2019).
Mechanism of action
Plerixafor acts as an antagonist to the chemokine receptor CXCR4 . This receptor is responsible for the targeted migration ( chemotaxis ) of stem cells towards higher concentrations of the CXCR4 ligand CXCL12 in the bone marrow. The receptor is blocked by binding plerixafor to parts of the ligand binding pocket of CXCR4 near the surface with the involvement of the transmembrane domains I, II, IV, VI and VII surrounding the binding pocket. In this way, Plerixafor blocks the binding of the N-terminal part of, which is essential for receptor activation CXCL12 into the ligand binding pocket. Subsequent signal transduction processes , which ultimately lead to a migration of CXCR4-positive stem cells and lymphocytes to higher CXCL12 concentrations, are interrupted.
It also inhibits the introduction of X4-tropic HI viruses into T cells . This is also done by blocking amino acid residues close to the surface of CXCR4, which like the chemokine receptor CCR5 has an HIV coreceptor function, and thus blocking the docking sites for the HIV glycoprotein gp120 . However, there is no drug approval for the indication HIV.
Contraindications
Plerixafor should not be used in patients with leukemia because Plerixafor can promote the release of leukemic cells.
pregnancy
Plerixaforer is teratogenic and foetotoxic in animal experiments . Therefore, pregnancy should be excluded prior to the use of plerixafora.
Side effects
The most common side effects of plerixafora use, with a frequency greater than 10%, are diarrhea, nausea, vomiting, tiredness, headache, joint pain, and injection site reactions. In addition, changes in the blood count with an increase in the leukocyte count and a decrease in the platelet count and a possible mobilization of tumor cells from the bone marrow are to be expected. Animal experiments also indicate a possible risk of rupture of the spleen .
Interactions
Interactions with other drugs are not yet known. Plerixafor is not an inhibitor of the cytochrome P450 enzyme system.
Individual evidence
- ↑ Data sheet AMD3100 octahydrochloride hydrate, ≥97% (NMR), solid from Sigma-Aldrich , accessed on February 24, 2013 ( PDF ).
- ↑ De Clercq E, Yamamoto N, Pauwels R, et al : Highly potent and selective inhibition of human immunodeficiency virus by the bicyclam derivative JM3100 . In: Antimicrob. Agents Chemother. . 38, No. 4, April 1994, pp. 668-674. PMID 7913308 . PMC 284523 (free full text).
- ↑ Hendrix CW, Flexner C, et al. : Pharmacokinetics and safety of AMD-3100, a novel antagonist of the CXCR-4 chemokine receptor, in human volunteers . Antimicrob Agents Chemother. 2000 Jun; 44 (6): 1667-1673, PMID 10817726 .
- ↑ FDA Approves Genzyme's Mozobil ( Memento of October 19, 2009 in the Internet Archive ) (Genzyme press release on the FDA approval of Mozobil of December 15, 2008).
- ↑ Esté JA, Cabrera C, De Clercq E, Struyf S, Van Damme J, Bridger G, Skerlj RT, Abrams MJ, Henson G, Gutierrez A, Clotet B, Schols D: Activity of different bicyclam derivatives against human immunodeficiency virus depends on their interaction with the CXCR4 chemokine receptor . In: Mol. Pharmacol. . 55, No. 1, January 1999, pp. 67-73. PMID 9882699 .
- ↑ Bridger G. et al. (1993): LINKED CYCLIC POLYAMINES WITH ACTIVITY AGAINST HIV. (Patent WO / 1993/012096 ).
- ↑ a b c d e US prescribing information by Mozobil ( Memento of February 6, 2009 in the Internet Archive ) (English).
- ↑ Summary of opinion (post authorization) - Mozobil plerixafor , PM EMA of March 28, 2019, accessed on April 9, 2019.
- ↑ European public assessment report (EPAR) for Mozobil , EMA, accessed on April 9, 2019.
- ^ David H McDermott, Diana V Pastrana, Katherine R Calvo, Stefania Pittaluga, Daniel Velez: Plerixafor for the Treatment of WHIM Syndrome . In: New England Journal of Medicine . tape 380 , no. 2 , January 10, 2019, p. 163-170 , doi : 10.1056 / NEJMoa1808575 .
- ↑ Wong RS, Bodart V, Metz M, Labrecque J, Bridger G, Fricker SP: Comparison of the potential multiple binding modes of bicyclam, monocylam, and noncyclam small-molecule CXC chemokine receptor 4 inhibitors . In: Mol. Pharmacol. . 74, No. 6, December 2008, pp. 1485-1495. doi : 10.1124 / mol.108.049775 . PMID 18768385 .