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Identification
NameAMD-070
Accession NumberDB05501
TypeSmall Molecule
GroupsInvestigational
Description

AMD-070 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 AMD-070, which targets the CXCR4 receptor on HIV and prevents the virus from entering and infecting healthy cells. Other entry inhibitors target the CCR5 receptor of HIV.These new agents are widely viewed as next generation anti-HIV drugs with the potential to significantly advance HIV therapeutics.

Structure
Thumb
SynonymsNot Available
External Identifiers Not Available
Approved Prescription ProductsNot Available
Approved Generic Prescription ProductsNot Available
Approved Over the Counter ProductsNot Available
Unapproved/Other Products Not Available
International BrandsNot Available
Brand mixturesNot Available
SaltsNot Available
Categories
UNII0G9LGB5O2W
CAS numberNot Available
WeightNot Available
Chemical FormulaNot Available
InChI KeyNot Available
InChINot Available
IUPAC NameNot Available
SMILESNot Available
Taxonomy
ClassificationNot classified
Pharmacology
IndicationInvestigated for use/treatment in HIV infection.
PharmacodynamicsAMD-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 actionChemokine 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
Related Articles
AbsorptionNot Available
Volume of distributionNot Available
Protein bindingNot Available
MetabolismNot Available
Route of eliminationNot Available
Half lifeNot Available
ClearanceNot Available
ToxicityNot Available
Affected organismsNot Available
PathwaysNot Available
SNP Mediated EffectsNot Available
SNP Mediated Adverse Drug ReactionsNot Available
ADMET
Predicted ADMET features
PropertyValueProbability
Human Intestinal AbsorptionNot AvailableNot Available
Blood Brain BarrierNot AvailableNot Available
Caco-2 permeableNot AvailableNot Available
P-glycoprotein substrateNot AvailableNot Available
P-glycoprotein inhibitor INot AvailableNot Available
P-glycoprotein inhibitor IINot AvailableNot Available
Renal organic cation transporterNot AvailableNot Available
CYP450 2C9 substrateNot AvailableNot Available
CYP450 2D6 substrateNot AvailableNot Available
CYP450 3A4 substrateNot AvailableNot Available
CYP450 1A2 substrateNot AvailableNot Available
CYP450 2C9 inhibitorNot AvailableNot Available
CYP450 2D6 inhibitorNot AvailableNot Available
CYP450 2C19 inhibitorNot AvailableNot Available
CYP450 3A4 inhibitorNot AvailableNot Available
CYP450 inhibitory promiscuityNot AvailableNot Available
Ames testNot AvailableNot Available
CarcinogenicityNot AvailableNot Available
BiodegradationNot AvailableNot Available
Rat acute toxicityNot AvailableNot applicable
hERG inhibition (predictor I)Not AvailableNot Available
hERG inhibition (predictor II)Not AvailableNot Available
ADMET data is predicted using admetSAR, a free tool for evaluating chemical ADMET properties. (23092397 )
Pharmacoeconomics
ManufacturersNot Available
PackagersNot Available
Dosage formsNot Available
PricesNot Available
PatentsNot Available
Properties
StateSolid
Experimental PropertiesNot Available
Predicted PropertiesNot Available
Spectra
Mass Spec (NIST)Not Available
Spectra
Spectrum TypeDescriptionSplash Key
References
Synthesis ReferenceNot Available
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. [PubMed:17452489 ]
  2. Reeves JD, Piefer AJ: Emerging drug targets for antiretroviral therapy. Drugs. 2005;65(13):1747-66. [PubMed:16114975 ]
  3. De Clercq E: Emerging anti-HIV drugs. Expert Opin Emerg Drugs. 2005 May;10(2):241-73. [PubMed:15934866 ]
  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. [PubMed:15892586 ]
  5. Huff B: HIV co-receptor drugs on the horizon. GMHC Treat Issues. 2004 Jul-Aug;18(7-8):7-8. [PubMed:15473043 ]
External Links
ATC CodesNot Available
AHFS CodesNot Available
PDB EntriesNot Available
FDA labelNot Available
MSDSNot Available
Interactions
Drug InteractionsNot Available
Food InteractionsNot Available

Targets

Kind
Protein
Organism
Human
Pharmacological action
unknown
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 ubiquitin; leading to enhanced intracellular calcium ions and reduced cellular cAMP levels. Involved in hematopoiesis and in cardiac ventricular septum formation. Also plays an essential role in vasculari...
Gene Name:
CXCR4
Uniprot ID:
P61073
Molecular Weight:
39745.055 Da
Kind
Protein
Organism
Human
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 role in the control of granulocytic lineage proliferation or differentiation. Acts as a coreceptor (CD4 being the primary receptor) for HIV-1 R5 isolates.(Microbial infection) Acts as a receptor for hu...
Gene Name:
CCR5
Uniprot ID:
P51681
Molecular Weight:
40523.645 Da
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Drug created on November 18, 2007 11:25 / Updated on August 17, 2016 12:24