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Identification
NamePradefovir Mesylate
Accession NumberDB05478
TypeSmall Molecule
GroupsInvestigational
Description

Pradefovir mesilate (previously known as MB-06886, Hepavir B and remofovir mesylate) is an orally administered small molecule compound that belongs to a novel series of phosphate and phosphonate prodrugs of adefovir. Adefovir (Hepsera) is an acyclic phosphonate analogue of adenine that is used to treat hepatitis B virus. As adefovir is poorly absorbed and associated with a high level of nephrotoxicity, pradefovir mesilate was designed to specifically target the liver and reduce risks to external tissue, especially the kidneys, while improving results of adefovir.
Pradefovir is activated through oxidation that is mediated by cytochrome P-450 (CYP) 3A4, which is predominantly expressed in the liver. The novel prodrug is highly stable in both plasma and tissues and demonstrated potent preclinical and clinical anti-HBV activity. Pradefovir is undergoing phase II development for the treatment of chronic hepatitis B.

Structure
Thumb
SynonymsNot Available
External Identifiers
  • MB-06886
Approved Prescription ProductsNot Available
Approved Generic Prescription ProductsNot Available
Approved Over the Counter ProductsNot Available
Unapproved/Other Products Not Available
International Brands
NameCompany
Hepavir BNot Available
remofovir mesylateNot Available
Brand mixturesNot Available
SaltsNot Available
Categories
UNII0D5204ZSIX
CAS numberNot Available
WeightAverage: 519.896
Monoisotopic: 519.074433024
Chemical FormulaC18H23ClN5O7PS
InChI KeyJXQUAHHUSMJUFV-HZPZRMRQSA-N
InChI
InChI=1S/C17H19ClN5O4P.CH4O3S/c18-13-3-1-2-12(8-13)14-4-6-26-28(24,27-14)11-25-7-5-23-10-22-15-16(19)20-9-21-17(15)23;1-5(2,3)4/h1-3,8-10,14H,4-7,11H2,(H2,19,20,21);1H3,(H,2,3,4)/t14-,28+;/m0./s1
IUPAC Name
(2R,4S)-2-{[2-(6-amino-9H-purin-9-yl)ethoxy]methyl}-4-(3-chlorophenyl)-1,3,2λ⁵-dioxaphosphinan-2-one; methanesulfonic acid
SMILES
CS(O)(=O)=O.NC1=C2N=CN(CCOC[P@@]3(=O)OCC[[email protected]](O3)C3=CC(Cl)=CC=C3)C2=NC=N1
Taxonomy
DescriptionThis compound belongs to the class of organic compounds known as 6-aminopurines. These are purines that carry an amino group at position 6. Purine is a bicyclic aromatic compound made up of a pyrimidine ring fused to an imidazole ring.
KingdomOrganic compounds
Super ClassOrganoheterocyclic compounds
ClassImidazopyrimidines
Sub ClassPurines and purine derivatives
Direct Parent6-aminopurines
Alternative Parents
Substituents
  • 6-aminopurine
  • Phosphonic acid diester
  • Halobenzene
  • Chlorobenzene
  • Aminopyrimidine
  • Imidolactam
  • Benzenoid
  • Pyrimidine
  • Primary aromatic amine
  • Phosphonic acid ester
  • N-substituted imidazole
  • Monocyclic benzene moiety
  • Aryl halide
  • Aryl chloride
  • Heteroaromatic compound
  • Alkanesulfonic acid
  • Sulfonyl
  • Sulfonic acid derivative
  • Sulfonic acid
  • Organophosphonic acid derivative
  • Methanesulfonate
  • Imidazole
  • Azole
  • Oxacycle
  • Azacycle
  • Hydrocarbon derivative
  • Primary amine
  • Organosulfur compound
  • Organophosphorus compound
  • Organooxygen compound
  • Organonitrogen compound
  • Organochloride
  • Organohalogen compound
  • Amine
  • Aromatic heteropolycyclic compound
  • Aliphatic acyclic compound
Molecular FrameworkNot Available
External DescriptorsNot Available
Pharmacology
IndicationInvestigated for use as a prodrug for Hepsera in treating hepatitis (viral, B).
PharmacodynamicsPradefovir is activated through oxidation that is mediated by cytochrome P-450 (CYP) 3A4, which is predominantly expressed in the liver. Accordingly, pradefovir allows Hepsera to be concentrated in the liver, while maintaining lower concentration levels in other tissue. The novel prodrug is an orally administered small molecule compound that belongs to a novel series of phosphate and phosphonate drugs. It is highly stable in both plasma and tissues.
Mechanism of actionPradefovir is activated through oxidation that is mediated by cytochrome P-450 (CYP) 3A4, which is predominantly expressed in the liver. In this way, it allows for increased Hepsera concentrations selectively in the liver.
Related Articles
AbsorptionNot Available
Volume of distributionNot Available
Protein bindingNot Available
MetabolismNot Available
Route of eliminationNot Available
Half lifeNot Available
ClearanceNot Available
ToxicityGood safety profile.
Affected organismsNot Available
PathwaysNot Available
SNP Mediated EffectsNot Available
SNP Mediated Adverse Drug ReactionsNot Available
ADMET
Predicted ADMET features
PropertyValueProbability
Human Intestinal Absorption+0.9215
Blood Brain Barrier+0.7057
Caco-2 permeable-0.5934
P-glycoprotein substrateSubstrate0.6577
P-glycoprotein inhibitor INon-inhibitor0.5801
P-glycoprotein inhibitor IINon-inhibitor0.9144
Renal organic cation transporterNon-inhibitor0.7104
CYP450 2C9 substrateNon-substrate0.8773
CYP450 2D6 substrateNon-substrate0.7879
CYP450 3A4 substrateSubstrate0.5813
CYP450 1A2 substrateNon-inhibitor0.6392
CYP450 2C9 inhibitorNon-inhibitor0.6918
CYP450 2D6 inhibitorNon-inhibitor0.8363
CYP450 2C19 inhibitorNon-inhibitor0.6393
CYP450 3A4 inhibitorNon-inhibitor0.5264
CYP450 inhibitory promiscuityHigh CYP Inhibitory Promiscuity0.5433
Ames testNon AMES toxic0.5622
CarcinogenicityNon-carcinogens0.5573
BiodegradationNot ready biodegradable0.9974
Rat acute toxicity2.5899 LD50, mol/kg Not applicable
hERG inhibition (predictor I)Strong inhibitor0.7783
hERG inhibition (predictor II)Inhibitor0.7366
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 Properties
PropertyValueSource
logP1.81ChemAxon
pKa (Strongest Acidic)18.59ChemAxon
pKa (Strongest Basic)5.13ChemAxon
Physiological Charge0ChemAxon
Hydrogen Acceptor Count6ChemAxon
Hydrogen Donor Count1ChemAxon
Polar Surface Area114.38 Å2ChemAxon
Rotatable Bond Count6ChemAxon
Refractivity104.06 m3·mol-1ChemAxon
Polarizability39.16 Å3ChemAxon
Number of Rings4ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleYesChemAxon
MDDR-like RuleYesChemAxon
Spectra
Mass Spec (NIST)Not Available
SpectraNot Available
References
Synthesis ReferenceNot Available
General References
  1. Reddy KR, Matelich MC, Ugarkar BG, Gomez-Galeno JE, DaRe J, Ollis K, Sun Z, Craigo W, Colby TJ, Fujitaki JM, Boyer SH, van Poelje PD, Erion MD: Pradefovir: a prodrug that targets adefovir to the liver for the treatment of hepatitis B. J Med Chem. 2008 Feb 14;51(3):666-76. doi: 10.1021/jm7012216. Epub 2008 Jan 4. [PubMed:18173234 ]
  2. Tillmann HL: Pradefovir, a liver-targeted prodrug of adefovir against HBV infection. Curr Opin Investig Drugs. 2007 Aug;8(8):682-90. [PubMed:17668370 ]
  3. Lin CC, Fang C, Benetton S, Xu GF, Yeh LT: Metabolic activation of pradefovir by CYP3A4 and its potential as an inhibitor or inducer. Antimicrob Agents Chemother. 2006 Sep;50(9):2926-31. [PubMed:16940083 ]
  4. Lin CC, Xu C, Teng A, Yeh LT, Peterson J: Pharmacokinetics of pradefovir and PMEA in healthy volunteers after oral dosing of pradefovir. J Clin Pharmacol. 2005 Nov;45(11):1250-8. [PubMed:16239358 ]
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:
Vitamin d3 25-hydroxylase activity
Specific Function:
Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It performs a variety of oxidation reactions (e.g. caffeine 8-oxidation, omeprazole sulphoxidation, midazolam 1'-hydroxylation and midazolam 4-hydroxylation) of structurally unrelated compounds, including steroids, fatty acids, and xenobiot...
Gene Name:
CYP3A4
Uniprot ID:
P08684
Molecular Weight:
57342.67 Da
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Drug created on November 18, 2007 11:25 / Updated on October 15, 2015 17:32