Mavorixafor

Identification

Generic Name
Mavorixafor
DrugBank Accession Number
DB05501
Background

Mavorixafor is a small molecule drug candidate that belongs to a new investigational class of anti-HIV drugs known as entry (fusion) inhibitors. Currently there is only one FDA-approved entry inhibitor, enfuvirtide (Fuzeon), that is available for the treatment of HIV infection. Several experimental entry inhibitors are now in early stage testing, including mavorixafor. Mavorixafor is a selective allosteric antagonist of the CXCR4 receptor on HIV, preventing the virus from entering and infecting healthy cells.

Type
Small Molecule
Groups
Investigational
Structure
Weight
Average: 349.482
Monoisotopic: 349.226645889
Chemical Formula
C21H27N5
Synonyms
  • 1,4-BUTANEDIAMINE, N1-(1H-BENZIMIDAZOL-2-YLMETHYL)-N1-((8S)-5,6,7,8-TETRAHYDRO-8-QUINOLINYL)-
  • N1-(1H-BENZIMIDAZOL-2-YLMETHYL)-N1-((S)-5,6,7,8-TETRAHYDROQUINOLIN-8-YL)-BUTANE-1,4-DIAMINE
External IDs
  • AMD-070
  • AMD-11070
  • AMD070
  • AMD11070
  • X4P 001
  • X4P-001
  • X4P001

Pharmacology

Indication

Investigated for use/treatment in HIV infection.

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Pharmacodynamics

AMD-070 is a small molecule drug candidate that belongs to a new investigational class of anti-HIV drugs known as entry (fusion) inhibitors. Approximately 76% of HIV-patients with measurable viral load are infected with a strain of virus that is resistant to one or more classes of antiretroviral agents, thus reducing treatment options. Unlike many existing HIV drugs that target the virus after it has infected a healthy cell, AMD-070 blocks the virus from entering a healthy cell, thus preventing the replication process. AMD-070 targets the CXCR4 receptor on HIV and prevents the virus from entering and infecting healthy cells. * AMD-070 is specific for the CXCR4 receptor and does not interact with any other chemokine receptors in vitro * AMD-070 strongly inhibits viral infection by all CXCR4 using virus (including virus using CXCR4 alone and/or virus using CXCR4 and CCR5) in vitro * AMD-070 is orally bioavailable in animals * Suitable PK and toxicity profile for oral dosing * AMD-070 shows additive or synergistic effects in vitro in combination with other known anti-HIV agents * AMD-070 is active against CXCR4 using HIV strains that are resistant to existing antiretroviral therapies in vitro * Potent anti-HIV activity against CXCR4-using laboratory strains and clinical isolates

Mechanism of action

Chemokine receptors expressed on the surface of immune cells are known to play a critical role in virus infection and transmission. CXCR4, and another chemokine receptor CCR5, are involved in HIV infection.

The process of HIV entry begins with binding of the viral envelope glycoprotein to both the CD4 receptor and one of only two chemokine receptors, and ends with fusion of viral and cell membranes. Viral entry provides novel therapeutic targets against HIV. To date, at least 3 sub classes of HIV viral entry/fusion inhibitors have emerged:

  1. CD4 binding or attachment - targets initial recognition and binding of the viral glycoprotein gp120 to the cell-surface CD4 antigen.
  2. Chemokine co-receptor binding - targets binding of virus to the CCR5 or CXCR4 co-receptor.
  3. Fusion Inhibition - targets the viral glycoprotein gp41 inhibiting the fusion of virus with the cell.

Different strains of HIV prefer one receptor or the other, or may use either receptor to infect cells.

* 35% of strains use both CXCR4 and CCR5
* 5% of strains are pure CXCR4 using
* 60% of strains are pure CCR5 using
* An infected individual may harbor different levels of both CXCR4 and CCR5 using virus
* CXCR4 using virus independently predicts CD4 decline and HIV clinical progression and is associated with earlier mortality
TargetActionsOrganism
UC-X-C chemokine receptor type 4
antagonist
inhibitor
Humans
UC-C chemokine receptor type 5Not AvailableHumans
Absorption

Not Available

Volume of distribution

Not Available

Protein binding

Not Available

Metabolism
Not Available
Route of elimination

Not Available

Half-life

Not Available

Clearance

Not Available

Adverse Effects
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Toxicity

Not Available

Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
This information should not be interpreted without the help of a healthcare provider. If you believe you are experiencing an interaction, contact a healthcare provider immediately. The absence of an interaction does not necessarily mean no interactions exist.
Not Available
Food Interactions
Not Available

Categories

Drug Categories
Chemical TaxonomyProvided by Classyfire
Description
This compound belongs to the class of organic compounds known as aminoquinolines and derivatives. These are organic compounds containing an amino group attached to a quinoline ring system.
Kingdom
Organic compounds
Super Class
Organoheterocyclic compounds
Class
Quinolines and derivatives
Sub Class
Aminoquinolines and derivatives
Direct Parent
Aminoquinolines and derivatives
Alternative Parents
Hydroquinolines / Benzimidazoles / Aralkylamines / Pyridines and derivatives / Benzenoids / Imidazoles / Heteroaromatic compounds / Trialkylamines / Azacyclic compounds / Monoalkylamines
show 1 more
Substituents
Amine / Aminoquinoline / Aralkylamine / Aromatic heteropolycyclic compound / Azacycle / Azole / Benzenoid / Benzimidazole / Heteroaromatic compound / Hydrocarbon derivative
show 9 more
Molecular Framework
Aromatic heteropolycyclic compounds
External Descriptors
Not Available
Affected organisms
Not Available

Chemical Identifiers

UNII
0G9LGB5O2W
CAS number
558447-26-0
InChI Key
WVLHHLRVNDMIAR-IBGZPJMESA-N
InChI
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
IUPAC Name
(8S)-N-(4-aminobutyl)-N-[(1H-1,3-benzodiazol-2-yl)methyl]-5,6,7,8-tetrahydroquinolin-8-amine
SMILES
NCCCCN(CC1=NC2=CC=CC=C2N1)[C@H]1CCCC2=C1N=CC=C2

References

General References
  1. Stone ND, Dunaway SB, Flexner C, Tierney C, Calandra GB, Becker S, Cao YJ, Wiggins IP, Conley J, MacFarland RT, Park JG, Lalama C, Snyder S, Kallungal B, Klingman KL, Hendrix CW: Multiple-dose escalation study of the safety, pharmacokinetics, and biologic activity of oral AMD070, a selective CXCR4 receptor inhibitor, in human subjects. Antimicrob Agents Chemother. 2007 Jul;51(7):2351-8. Epub 2007 Apr 23. [Article]
  2. Reeves JD, Piefer AJ: Emerging drug targets for antiretroviral therapy. Drugs. 2005;65(13):1747-66. [Article]
  3. De Clercq E: Emerging anti-HIV drugs. Expert Opin Emerg Drugs. 2005 May;10(2):241-73. [Article]
  4. Castagna A, Biswas P, Beretta A, Lazzarin A: The appealing story of HIV entry inhibitors : from discovery of biological mechanisms to drug development. Drugs. 2005;65(7):879-904. [Article]
  5. Huff B: HIV co-receptor drugs on the horizon. GMHC Treat Issues. 2004 Jul-Aug;18(7-8):7-8. [Article]
PubChem Compound
11256587
PubChem Substance
347827734
ChemSpider
9431613
BindingDB
50315305
ChEBI
138865
ChEMBL
CHEMBL518924
ZINC
ZINC000033359232

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
3Active Not RecruitingTreatmentWHIM Syndrome1
3Not Yet RecruitingTreatmentNeutropenia1
2CompletedTreatmentWHIM Syndrome1
1CompletedTreatmentHuman Immunodeficiency Virus (HIV) Infections1
1CompletedTreatmentHuman Immunodeficiency Virus (HIV) Infections / X4 Tropic Virus1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage Forms
Not Available
Prices
Not Available
Patents
Not Available

Properties

State
Solid
Experimental Properties
Not Available
Predicted Properties
PropertyValueSource
Water Solubility0.0284 mg/mLALOGPS
logP2.61ALOGPS
logP2.61Chemaxon
logS-4.1ALOGPS
pKa (Strongest Acidic)11.5Chemaxon
pKa (Strongest Basic)10.18Chemaxon
Physiological Charge2Chemaxon
Hydrogen Acceptor Count4Chemaxon
Hydrogen Donor Count2Chemaxon
Polar Surface Area70.83 Å2Chemaxon
Rotatable Bond Count7Chemaxon
Refractivity104.49 m3·mol-1Chemaxon
Polarizability41.01 Å3Chemaxon
Number of Rings4Chemaxon
Bioavailability1Chemaxon
Rule of FiveYesChemaxon
Ghose FilterYesChemaxon
Veber's RuleNoChemaxon
MDDR-like RuleYesChemaxon
Predicted ADMET Features
Not Available

Spectra

Mass Spec (NIST)
Not Available
Spectra
SpectrumSpectrum TypeSplash Key
Predicted MS/MS Spectrum - 10V, Positive (Annotated)Predicted LC-MS/MSsplash10-0udi-0009000000-8ec41bdfc781460b4184
Predicted MS/MS Spectrum - 10V, Negative (Annotated)Predicted LC-MS/MSsplash10-0002-0129000000-2f1e27070ffb5d2bcc91
Predicted MS/MS Spectrum - 20V, Positive (Annotated)Predicted LC-MS/MSsplash10-0f89-0109000000-02d1bb52c4b3346bc09b
Predicted MS/MS Spectrum - 20V, Negative (Annotated)Predicted LC-MS/MSsplash10-0002-0139000000-d20eaef4e857f92f1541
Predicted MS/MS Spectrum - 40V, Positive (Annotated)Predicted LC-MS/MSsplash10-001i-0972000000-4fa38c8e2b096f1199aa
Predicted MS/MS Spectrum - 40V, Negative (Annotated)Predicted LC-MS/MSsplash10-0002-0900000000-544ec10b25a5f6740ecf
Predicted 1H NMR Spectrum1D NMRNot Applicable
Predicted 13C NMR Spectrum1D NMRNot Applicable
Chromatographic Properties
Collision Cross Sections (CCS)
AdductCCS Value (Å2)Source typeSource
[M-H]-181.77473
predicted
DeepCCS 1.0 (2019)
[M+H]+184.13275
predicted
DeepCCS 1.0 (2019)
[M+Na]+191.79967
predicted
DeepCCS 1.0 (2019)

Targets

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Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Antagonist
Inhibitor
General Function
Virus receptor activity
Specific Function
Receptor for the C-X-C chemokine CXCL12/SDF-1 that transduces a signal by increasing intracellular calcium ion levels and enhancing MAPK1/MAPK3 activation. Acts as a receptor for extracellular ubiq...
Gene Name
CXCR4
Uniprot ID
P61073
Uniprot Name
C-X-C chemokine receptor type 4
Molecular Weight
39745.055 Da
References
  1. Castillo JJ, Treon SP: Management of Waldenstrom macroglobulinemia in 2020. Hematology Am Soc Hematol Educ Program. 2020 Dec 4;2020(1):372-379. doi: 10.1182/hematology.2020000121. [Article]
  2. De Clercq E: Emerging anti-HIV drugs. Expert Opin Emerg Drugs. 2005 May;10(2):241-73. [Article]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
General Function
Virus receptor activity
Specific Function
Receptor for a number of inflammatory CC-chemokines including MIP-1-alpha, MIP-1-beta and RANTES and subsequently transduces a signal by increasing the intracellular calcium ion level. May play a r...
Gene Name
CCR5
Uniprot ID
P51681
Uniprot Name
C-C chemokine receptor type 5
Molecular Weight
40523.645 Da

Drug created at November 18, 2007 18:25 / Updated at July 07, 2023 12:10