PRADEFOVIR MESYLATE

Details

Stereochemistry	ABSOLUTE
Molecular Formula	C17H19ClN5O4P.CH4O3S
Molecular Weight	519.896
Optical Activity	UNSPECIFIED
Defined Stereocenters	2 / 2
E/Z Centers	0
Charge	0

SHOW SMILES / InChI

Structure Search

SMILES

CS(O)(=O)=O.NC1=C2N=CN(CCOC[P@@]3(=O)OCC[C@H](O3)C4=CC=CC(Cl)=C4)C2=NC=N1

InChI

InChIKey=JXQUAHHUSMJUFV-HZPZRMRQSA-N

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

HIDE SMILES / InChI

Description
Sources: http://www.accessdata.fda.gov/drugsatfda_docs/label/2012/021449s020lbl.pdf
Curator's Comment: Description was created based on several sources, including: https://www.ncbi.nlm.nih.gov/pubmed/14498759 http://link.springer.com/chapter/10.1007%2F978-0-387-49785-3_33

The potential antiviral effect of adefovir, an acyclic nucleoside phosphonate analog of 2′-deoxyadenosine monophosphate, was first studied by Holý and De Clercq in 1980s. Adefovir is an acyclic nucleotide analog of adenosine monophosphate which is phosphorylated to the active metabolite adefovir diphosphate by cellular kinases. Adefovir diphosphate inhibits HBV DNA polymerase (reverse transcriptase) by competing with the natural substrate deoxyadenosine triphosphate and by causing DNA chain termination after its incorporation into viral DNA. Oral adefovir dipivoxil is effective and generally well tolerated in HBeAg-positive and -negative patients chronically infected with wild-type or lamivudine-resistant HBV.

CNS Activity

Originator

Approval Year

Targets

Primary Target	Pharmacology	Potency
Multidrug resistance-associated protein 4 14 Target ID: CHEMBL1743128 Sources: https://www.ncbi.nlm.nih.gov/pubmed/23956101	Inhibitor 8297	133.0 µM [IC50]
Bile salt export pump 15 Target ID: CHEMBL6020 Sources: https://www.ncbi.nlm.nih.gov/pubmed/23956101	Inhibitor 8297	46.0 µM [IC50]
Canalicular multispecific organic anion transporter 1 21 Target ID: CHEMBL5748 Sources: https://www.ncbi.nlm.nih.gov/pubmed/23956101	Inhibitor 8297	133.0 µM [IC50]
Canalicular multispecific organic anion transporter 2 8 Target ID: CHEMBL5918 Sources: https://www.ncbi.nlm.nih.gov/pubmed/23956101	Inhibitor 8297	133.0 µM [IC50]
DNA polymerase/reverse transcriptase 10 Target ID: CHEMBL2362994 Sources: http://www.accessdata.fda.gov/drugsatfda_docs/label/2012/021449s020lbl.pdf	Inhibitor 8297	0.1 µM [Ki]

Conditions

Condition	Modality	Targets	Highest Phase	Product
Chronic hepatitis B 16 Sources: http://www.accessdata.fda.gov/drugsatfda_docs/label/2012/021449s020lbl.pdf	Primary		Approved 8429	HEPSERA Approved Use HEPSERA is indicated for the treatment of chronic hepatitis B in patients 12 years of age and older with evidence of active viral replication and either evidence of persistent elevations in serum aminotransferases (ALT or AST) or histologically active disease. This indication is based on histological, virological, biochemical, and serological responses in adult patients with HBeAg+ and HBeAg- chronic hepatitis B with compensated liver function, and with clinical evidence of lamivudine-resistant hepatitis B virus with either compensated or decompensated liver function. For patients 12 to <18 years of age, the indication is based on virological and biochemical responses in patients with HBeAg+ chronic hepatitis B virus infection with compensated liver function. HEPSERA is a nucleotide analogue indicated for the treatment of chronic hepatitis B in patients ≥12 years of age. (1) Launch Date 2002

C_max

Value	Dose	Co-administered	Analyte	Population
18.4 ng/mL DRUG LABEL https://www.accessdata.fda.gov/drugsatfda_docs/label/2006/021449s009lbl.pdf	10 mg single, oral dose: 10 mg route of administration: Oral experiment type: SINGLE co-administered:		ADEFOVIR plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: UNKNOWN food status: UNKNOWN

AUC

Value	Dose	Co-administered	Analyte	Population
220 ng × h/mL DRUG LABEL https://www.accessdata.fda.gov/drugsatfda_docs/label/2006/021449s009lbl.pdf	10 mg single, oral dose: 10 mg route of administration: Oral experiment type: SINGLE co-administered:		ADEFOVIR plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: UNKNOWN food status: UNKNOWN

T_1/2

Value	Dose	Co-administered	Analyte	Population
7.48 h DRUG LABEL https://www.accessdata.fda.gov/drugsatfda_docs/label/2006/021449s009lbl.pdf	10 mg single, oral dose: 10 mg route of administration: Oral experiment type: SINGLE co-administered:		ADEFOVIR plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: UNKNOWN food status: UNKNOWN

F_unbound

Value	Dose	Co-administered	Analyte	Population
96% DRUG LABEL https://www.accessdata.fda.gov/drugsatfda_docs/label/2006/021449s009lbl.pdf	10 mg single, oral dose: 10 mg route of administration: Oral experiment type: SINGLE co-administered:		ADEFOVIR plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: UNKNOWN food status: UNKNOWN

Doses

Dose	Population	Adverse events
10 mg 1 times / day multiple, oral Recommended Dose: 10 mg, 1 times / day Route: oral Route: multiple Dose: 10 mg, 1 times / day Sources: https://pubmed.ncbi.nlm.nih.gov/18276803/	unhealthy, 12 - 17 years n = 15 Health Status: unhealthy Condition: chronic hepatitis B Age Group: 12 - 17 years Sex: M+F Population Size: 15 Sources: https://pubmed.ncbi.nlm.nih.gov/18276803/	Other AEs: Rhinorrhea, Sneezing... Other AEs: Rhinorrhea (1 patient) Sneezing (1 patient) Blister (1 patient) Sources: https://pubmed.ncbi.nlm.nih.gov/18276803/
0.3 mg/kg 1 times / day multiple, oral Recommended Dose: 0.3 mg/kg, 1 times / day Route: oral Route: multiple Dose: 0.3 mg/kg, 1 times / day Sources: https://pubmed.ncbi.nlm.nih.gov/18276803/	unhealthy, 2 - 6 years n = 13 Health Status: unhealthy Condition: chronic hepatitis B Age Group: 2 - 6 years Sex: M+F Population Size: 13 Sources: https://pubmed.ncbi.nlm.nih.gov/18276803/	Sources: https://pubmed.ncbi.nlm.nih.gov/18276803/
0.3 mg/kg 1 times / day multiple, oral Recommended Dose: 0.3 mg/kg, 1 times / day Route: oral Route: multiple Dose: 0.3 mg/kg, 1 times / day Sources: https://pubmed.ncbi.nlm.nih.gov/18276803/	unhealthy, 7 - 11 years n = 19 Health Status: unhealthy Condition: chronic hepatitis B Age Group: 7 - 11 years Sex: M+F Population Size: 19 Sources: https://pubmed.ncbi.nlm.nih.gov/18276803/	Other AEs: Headache, Vertigo... Other AEs: Headache (1 patient) Vertigo (1 patient) Disturbance in attention (1 patient) Disorder eye (1 patient) Sources: https://pubmed.ncbi.nlm.nih.gov/18276803/

AEs

AE	Significance	Dose	Population
Blister	1 patient	10 mg 1 times / day multiple, oral Recommended Dose: 10 mg, 1 times / day Route: oral Route: multiple Dose: 10 mg, 1 times / day Sources: https://pubmed.ncbi.nlm.nih.gov/18276803/	unhealthy, 12 - 17 years n = 15 Health Status: unhealthy Condition: chronic hepatitis B Age Group: 12 - 17 years Sex: M+F Population Size: 15 Sources: https://pubmed.ncbi.nlm.nih.gov/18276803/
Rhinorrhea	1 patient	10 mg 1 times / day multiple, oral Recommended Dose: 10 mg, 1 times / day Route: oral Route: multiple Dose: 10 mg, 1 times / day Sources: https://pubmed.ncbi.nlm.nih.gov/18276803/	unhealthy, 12 - 17 years n = 15 Health Status: unhealthy Condition: chronic hepatitis B Age Group: 12 - 17 years Sex: M+F Population Size: 15 Sources: https://pubmed.ncbi.nlm.nih.gov/18276803/
Sneezing	1 patient	10 mg 1 times / day multiple, oral Recommended Dose: 10 mg, 1 times / day Route: oral Route: multiple Dose: 10 mg, 1 times / day Sources: https://pubmed.ncbi.nlm.nih.gov/18276803/	unhealthy, 12 - 17 years n = 15 Health Status: unhealthy Condition: chronic hepatitis B Age Group: 12 - 17 years Sex: M+F Population Size: 15 Sources: https://pubmed.ncbi.nlm.nih.gov/18276803/
Disorder eye	1 patient	0.3 mg/kg 1 times / day multiple, oral Recommended Dose: 0.3 mg/kg, 1 times / day Route: oral Route: multiple Dose: 0.3 mg/kg, 1 times / day Sources: https://pubmed.ncbi.nlm.nih.gov/18276803/	unhealthy, 7 - 11 years n = 19 Health Status: unhealthy Condition: chronic hepatitis B Age Group: 7 - 11 years Sex: M+F Population Size: 19 Sources: https://pubmed.ncbi.nlm.nih.gov/18276803/
Disturbance in attention	1 patient	0.3 mg/kg 1 times / day multiple, oral Recommended Dose: 0.3 mg/kg, 1 times / day Route: oral Route: multiple Dose: 0.3 mg/kg, 1 times / day Sources: https://pubmed.ncbi.nlm.nih.gov/18276803/	unhealthy, 7 - 11 years n = 19 Health Status: unhealthy Condition: chronic hepatitis B Age Group: 7 - 11 years Sex: M+F Population Size: 19 Sources: https://pubmed.ncbi.nlm.nih.gov/18276803/
Headache	1 patient	0.3 mg/kg 1 times / day multiple, oral Recommended Dose: 0.3 mg/kg, 1 times / day Route: oral Route: multiple Dose: 0.3 mg/kg, 1 times / day Sources: https://pubmed.ncbi.nlm.nih.gov/18276803/	unhealthy, 7 - 11 years n = 19 Health Status: unhealthy Condition: chronic hepatitis B Age Group: 7 - 11 years Sex: M+F Population Size: 19 Sources: https://pubmed.ncbi.nlm.nih.gov/18276803/
Vertigo	1 patient	0.3 mg/kg 1 times / day multiple, oral Recommended Dose: 0.3 mg/kg, 1 times / day Route: oral Route: multiple Dose: 0.3 mg/kg, 1 times / day Sources: https://pubmed.ncbi.nlm.nih.gov/18276803/	unhealthy, 7 - 11 years n = 19 Health Status: unhealthy Condition: chronic hepatitis B Age Group: 7 - 11 years Sex: M+F Population Size: 19 Sources: https://pubmed.ncbi.nlm.nih.gov/18276803/

Overview

CYP3A4	CYP2C9	CYP2D6	hERG
inhibitor 1587 substrate 1737	inhibitor 1767 substrate 1037	inhibitor 1852 substrate 1217

OverviewOther

Other Inhibitor	Other Substrate	Other Inducer
CYP1A2 1524 CYP2C19 1478 P-gp 1461	OAT1 326 OCT2 355 MRP4 77 CYP1A2 1054 CYP2C19 991 P-gp 1537	CYP 76

Drug as perpetrator

Target	Modality	Activity
CYP 147	inducer 1573 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2002/21-449_Hepsera_biopharmr_P1.pdf Page: 6, 16	inconclusive
P-gp 1650	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2002/21-449_Hepsera_biopharmr_P2.pdf Page: 26.0	inconclusive
CYP1A2 1692	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2002/21-449_Hepsera_biopharmr_P1.pdf Page: 15.0	no
CYP2C19 1553	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2002/21-449_Hepsera_biopharmr_P1.pdf Page: 15.0	no
CYP2C9 1819	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2002/21-449_Hepsera_biopharmr_P1.pdf Page: 15.0	no
CYP2D6 1891	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2002/21-449_Hepsera_biopharmr_P1.pdf Page: 15.0	no
CYP3A4 1925	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2002/21-449_Hepsera_biopharmr_P1.pdf Page: 15.0	no

Drug as victim

Target	Modality	Activity
P-gp 1537	substrate 3367 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2002/21-449_Hepsera_biopharmr_P2.pdf Page: 26.0	inconclusive
CYP1A2 1054	substrate 3367 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2002/21-449_Hepsera_biopharmr_P1.pdf Page: 15.0	no
CYP2C19 991	substrate 3367 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2002/21-449_Hepsera_biopharmr_P1.pdf Page: 15.0	no
CYP2C9 1037	substrate 3367 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2002/21-449_Hepsera_biopharmr_P1.pdf Page: 15.0	no
CYP2D6 1217	substrate 3367 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2002/21-449_Hepsera_biopharmr_P1.pdf Page: 15.0	no
CYP3A4 1737	substrate 3367 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2002/21-449_Hepsera_biopharmr_P1.pdf Page: 15.0	no
OCT2 355	substrate 3367 Sources: https://pubmed.ncbi.nlm.nih.gov/16454695/	no
MRP4 77	substrate 3367 Sources: https://pubmed.ncbi.nlm.nih.gov/16454695/	yes
OAT1 326	substrate 3367 Sources: https://pubmed.ncbi.nlm.nih.gov/16454695/	yes

Sourcing

Vendor/Aggregator	ID	URL
ChEBI	CHEBI:2469	https://www.ebi.ac.uk/chebi/searchId.do?chebiId=CHEBI:2469
ChemicalBook	CB2698137	https://www.chemicalbook.com/ChemicalProductProperty_EN_CB2698137
ZINC	ZINC000021297308	http://zinc15.docking.org/substances/ZINC000021297308
eMolecules	901335	https://www.emolecules.com/cgi-bin/more?vid=901335

PubMed

Title	Date	PubMed
9-[(2RS)-3-fluoro-2-phosphonylmethoxypropyl] derivatives of purines: a class of highly selective antiretroviral agents in vitro and in vivo.	1991 Jun 1	1711214
Synthesis and in vitro evaluation of a phosphonate prodrug: bis(pivaloyloxymethyl) 9-(2-phosphonylmethoxyethyl)adenine.	1992 Sep	1332606
Effect of acyclic nucleoside phosphonates on the HIV-1 integrase in vitro.	1999 Apr-May	10432692
Hydroxyurea potentiates the antiherpesvirus activities of purine and pyrimidine nucleoside and nucleoside phosphonate analogs.	1999 Dec	10582877
Sensitivity of L-(-)2,3-dideoxythiacytidine resistant hepatitis B virus to other antiviral nucleoside analogues.	1999 Jun 15	10353255
Prevalence and characteristics of multinucleoside-resistant human immunodeficiency virus type 1 among European patients receiving combinations of nucleoside analogues.	2000 Aug	10898683
Lamivudine, adefovir and tenofovir exhibit long-lasting anti-hepatitis B virus activity in cell culture.	2000 Jan	10718947
Drug resistance and drug combination features of the human immunodeficiency virus inhibitor, BCH-10652 [(+/-)-2'-deoxy-3'-oxa-4'-thiocytidine, dOTC].	2000 Jul	10950391
In vitro selection of mutations in the human immunodeficiency virus type 1 reverse transcriptase that decrease susceptibility to (-)-beta-D-dioxolane-guanosine and suppress resistance to 3'-azido-3'-deoxythymidine.	2000 Jul	10858331
A new acyclic heterodinucleotide active against human immunodeficiency virus and herpes simplex virus.	2000 Sep	10974367
Synthesis and evaluation of novel amidate prodrugs of PMEA and PMPA.	2001 Apr 23	11327587
Acute liver graft failure due to emergence of lamivudine resistant hepatitis B virus: rapid resolution during treatment with adefovir.	2001 Dec	11709523
Cross-resistance testing of antihepadnaviral compounds using novel recombinant baculoviruses which encode drug-resistant strains of hepatitis B virus.	2001 Jun	11353615
Intramolecular stacking interactions in ternary copper(II) complexes formed with 2,2'-bipyridine or 1,10-phenanthroline and 9-(4-phosphonobutyl)adenine (dPMEA), the carba relative of the antiviral nucleotide analogue 9.	2001 Mar	11330480
In vitro susceptibilities of wild-type or drug-resistant hepatitis B virus to (-)-beta-D-2,6-diaminopurine dioxolane and 2'-fluoro-5-methyl-beta-L-arabinofuranosyluracil.	2001 Sep	11502520
Fanconi syndrome and renal failure induced by tenofovir: a first case report.	2002 Dec	12460055
Antivaccinia activities of acyclic nucleoside phosphonate derivatives in epithelial cells and organotypic cultures.	2002 Nov	12384336
In vitro activity of potential anti-poxvirus agents.	2003 Jan	12615301
Intrinsic acid-base properties of purine derivatives in aqueous solution and comparison of the acidifying effects of platinum(II) coordinated to N1 or N7: acidifying effects are reciprocal and the proton "outruns" divalent metal ions.	2003 Jan 13	12513075
Evaluation of nucleoside phosphonates and their analogs and prodrugs for inhibition of orthopoxvirus replication.	2003 Jul	12821467
Nickel(II), copper(II) and zinc(II) complexes of 9-[2- (phosphonomethoxy)ethyl]-8-azaadenine (9,8aPMEA), the 8-aza derivative of the antiviral nucleotide analogue 9-[2-(phosphonomethoxy)ethyl] adenine (PMEA). Quantification of four isomeric species in aqueous solution.	2004	18365084
Intramolecular stacking interactions in ternary copper(II) complexes formed by a heteroaromatic amine and 9-[2-(2-phosphonoethoxy)ethyl]adenine, a relative of the antiviral nucleotide analogue 9-[2-(phosphonomethoxy)ethyl]adenine.	2004 Dec	15541501
Synthesis and antiviral activity of 2,4-diamino-5-cyano-6-[2-(phosphonomethoxy)ethoxy]pyrimidine and related compounds.	2004 Jun 15	15158787
In vitro selection of drug-resistant varicella-zoster virus (VZV) mutants (OKA strain): differences between acyclovir and penciclovir?	2004 Mar	15168799
Metal ion complexes of antivirally active nucleotide analogues. Conclusions regarding their biological action.	2004 Mar 30	15026824
6-[2-phosphonomethoxy)alkoxy]-2,4-diaminopyrimidines: a new class of acyclic pyrimidine nucleoside phosphonates with antiviral activity.	2004 Oct	15571252
Combinations of adefovir with nucleoside analogs produce additive antiviral effects against hepatitis B virus in vitro.	2004 Oct	15388423
Cross-resistance testing of next-generation nucleoside and nucleotide analogues against lamivudine-resistant HBV.	2005	16152756
Acid-base and metal-ion-binding properties of 9-[2-(2-phosphonoethoxy)ethyl]adenine (PEEA), a relative of the antiviral nucleotide analogue 9-[2-(phosphonomethoxy)ethyl]adenine (PMEA). An exercise on the quantification of isomeric complex equilibria in solution.	2005 Jul 11	15998039
Inhibition of human liver microsomal cytochrome P450 activities by adefovir and tenofovir.	2006 Dec	17162464
Synthesis, in vitro antiviral evaluation, and stability studies of novel alpha-borano-nucleotide analogues of 9-[2-(phosphonomethoxy)ethyl]adenine and (R)-9-[2-(phosphonomethoxy)propyl]adenine.	2006 Dec 28	17181162
Improved outcome of chronic hepatitis B after heart transplantation by long-term antiviral therapy.	2006 Nov	17052272
Synthesis and antiviral evaluation of alkoxyalkyl esters of acyclic purine and pyrimidine nucleoside phosphonates against HIV-1 in vitro.	2006 Oct	16630664
Decompensated lamivudine-resistant hepatitis B virus-related cirrhosis treated successfully with adefovir dipivoxil allowing surgery for hepatocellular carcinoma.	2007	17409599
Sequential emergence and clinical implications of viral mutants with K70E and K65R mutation in reverse transcriptase during prolonged tenofovir monotherapy in rhesus macaques with chronic RT-SHIV infection.	2007 Apr 6	17417971
Pronounced in vitro and in vivo antiretroviral activity of 5-substituted 2,4-diamino-6-[2-(phosphonomethoxy)ethoxy] pyrimidines.	2007 Jan	17124193
Design and synthesis of novel bis(L-amino acid) ester prodrugs of 9-[2-(phosphonomethoxy)ethyl]adenine (PMEA) with improved anti-HBV activity.	2007 Jan 15	17074481
Substrate overlap between Mrp4 and Abcg2/Bcrp affects purine analogue drug cytotoxicity and tissue distribution.	2007 Jul 15	17638908
Secretion of antiretroviral chemokines by human cells cultured with acyclic nucleoside phosphonates.	2007 Nov 21	17716649
In vitro drug susceptibility analysis of hepatitis B virus clinical quasispecies populations.	2007 Oct	17687019
Combination therapy in liver transplant recipients with hepatitis B virus without hepatitis B immune globulin.	2007 Oct	17404847
Gene induction for the treatment of methylmalonic aciduria.	2009 Apr	19199343
Renal side effects of adefovir in hepatitis B virus-(HBV) positive kidney allograft recipients.	2009 Jan	19203548

Patents

Sample Use Guides

In Vivo Use Guide

One tablet containing 10 mg adefovir dipivoxil once daily orally

Route of Administration: Oral

In Vitro Use Guide

The concentration of adefovir that inhibited 50% of viral DNA synthesis (EC50) in HBV transfected human hepatoma cell lines ranged from 0.2 to 2.5 uM.

Name

Type

Language

PRADEFOVIR MESYLATE

Official Name

English

PRADEFOVIR MESYLATE [USAN]

Common Name

English

Pradefovir mesilate [WHO-DD]

Common Name

English

PRADEFOVIR MESILATE

Common Name

English

Classification Tree Code System Code

NCI_THESAURUS

C1557