Pradefovir Mesylate

Identification

Name
Pradefovir Mesylate
Accession Number
DB05478
Type
Small Molecule
Groups
Investigational
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
Synonyms
  • Pradefovir mesilate
External IDs
MB-06886
International/Other Brands
Hepavir B / remofovir mesylate
Categories
UNII
0D5204ZSIX
CAS number
Not Available
Weight
Average: 519.896
Monoisotopic: 519.074433024
Chemical Formula
C18H23ClN5O7PS
InChI Key
JXQUAHHUSMJUFV-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[[email protected]@]3(=O)OCC[[email protected]](O3)C3=CC(Cl)=CC=C3)C2=NC=N1

Pharmacology

Indication

Investigated for use as a prodrug for Hepsera in treating hepatitis (viral, B).

Structured Indications
Not Available
Pharmacodynamics

Pradefovir 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 action

Pradefovir 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.

TargetActionsOrganism
UCytochrome P450 3A4Not AvailableHuman
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
Toxicity

Good safety profile.

Affected organisms
Not Available
Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
Not Available
Food Interactions
Not Available

References

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
PubChem Compound
9604653
PubChem Substance
175427015
ChemSpider
7878772

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
2CompletedTreatmentHepatitis B,Chronic1
2TerminatedTreatmentHepatitis B,Chronic1

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
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 FiveNoChemAxon
Ghose FilterNoChemAxon
Veber's RuleNoChemAxon
MDDR-like RuleYesChemAxon
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)

Spectra

Mass Spec (NIST)
Not Available
Spectra
SpectrumSpectrum TypeSplash Key
Predicted MS/MS Spectrum - 10V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 10V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Negative (Annotated)Predicted LC-MS/MSNot Available

Taxonomy

Description
This 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.
Kingdom
Organic compounds
Super Class
Organoheterocyclic compounds
Class
Imidazopyrimidines
Sub Class
Purines and purine derivatives
Direct Parent
6-aminopurines
Alternative Parents
Aminopyrimidines and derivatives / Chlorobenzenes / Dialkyl alkylphosphonates / Aryl chlorides / Phosphonic acid esters / Imidolactams / N-substituted imidazoles / Heteroaromatic compounds / Azacyclic compounds / Oxacyclic compounds
show 7 more
Substituents
6-aminopurine / Halobenzene / Phosphonic acid diester / Chlorobenzene / Dialkyl alkylphosphonate / Aminopyrimidine / Monocyclic benzene moiety / N-substituted imidazole / Imidolactam / Benzenoid
show 23 more
Molecular Framework
Not Available
External Descriptors
Not 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 react...
Gene Name
CYP3A4
Uniprot ID
P08684
Uniprot Name
Cytochrome P450 3A4
Molecular Weight
57342.67 Da

Drug created on November 18, 2007 11:25 / Updated on December 01, 2017 15:36