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Chemistry

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Also known as: 106941-25-7, Pmea, ((2-(6-amino-9h-purin-9-yl)ethoxy)methyl)phosphonic acid, 9-(2-phosphonylmethoxyethyl)adenine, Gs 0393, Gs-0393

Molecular Formula

C₈H₁₂N₅O₄P

Molecular Weight

273.19 g/mol

InChI Key

SUPKOOSCJHTBAH-UHFFFAOYSA-N

FDA UNII

6GQP90I798

Adefovir is a nucleoside reverse transcriptase inhibitor analog of adenosine with activity against hepatitis B virus (HBV), herpes virus, and human immunodeficiency virus (HIV).

Adefovir is a Hepatitis B Virus Nucleoside Analog Reverse Transcriptase Inhibitor. The mechanism of action of adefovir is as a Nucleoside Reverse Transcriptase Inhibitor.

1 2D Structure

Adefovir

2 Identification

2.1 Computed Descriptors

2.1.1 IUPAC Name

2-(6-aminopurin-9-yl)ethoxymethylphosphonic acid

2.1.2 InChI

InChI=1S/C8H12N5O4P/c9-7-6-8(11-3-10-7)13(4-12-6)1-2-17-5-18(14,15)16/h3-4H,1-2,5H2,(H2,9,10,11)(H2,14,15,16)

2.1.3 InChI Key

SUPKOOSCJHTBAH-UHFFFAOYSA-N

2.1.4 Canonical SMILES

C1=NC(=C2C(=N1)N(C=N2)CCOCP(=O)(O)O)N

2.2 Other Identifiers

2.2.1 UNII

6GQP90I798

2.3 Synonyms

2.3.1 MeSH Synonyms

1. 9-(2-phosphonomethoxyethyl)adenine

2. 9-(2-phosphonylmethoxyethyl)adenine

3. 9-pmea

2.3.2 Depositor-Supplied Synonyms

1. 106941-25-7

2. Pmea

3. ((2-(6-amino-9h-purin-9-yl)ethoxy)methyl)phosphonic Acid

4. 9-(2-phosphonylmethoxyethyl)adenine

5. Gs 0393

6. Gs-0393

7. 9-(2-(phosphonomethoxy)ethyl)adenine

8. Gs 393

9. Drg-0156

10. N-(2-phosphonylmethoxyethyl)adenine

11. {[2-(6-amino-9h-purin-9-yl)ethoxy]methyl}phosphonic Acid

12. 2-(6-aminopurin-9-yl)ethoxymethylphosphonic Acid

13. Hsdb 8079

14. Chembl484

15. Phosphonic Acid, [[2-(6-amino-9h-purin-9-yl)ethoxy]methyl]-

16. 6gqp90i798

17. 106941-25-7 (free Acid)

18. 9-[2-(phosphonomethoxy)ethyl]adenine

19. (2-(6-amino-9h-purin-9-yl)ethoxy)methylphosphonic Acid

20. Ncgc00160539-01

21. Phosphonic Acid, ((2-(6-amino-9h-purin-9-yl)ethoxy)methyl)-

22. [2-(6-amino-9h-purin-9-yl)ethoxy]methylphosphonic Acid

23. Brn 3561094

24. [[2-(6-amino-9h-purin-9-yl)ethoxy]methyl]phosphonic Acid

25. Adefovir [usan:inn:ban]

26. Unii-6gqp90i798

27. N-(2-phophonomethoxyethyl-2,6-diaminopurine)

28. Adefovir(1-)

29. Mfcd00866943

30. Adefovir [usan]

31. Adefovir (usan/inn)

32. Adefovir [inn]

33. Adefovir [mi]

34. Adefovir [vandf]

35. Adefovir [mart.]

36. Amd3100 And Pmea

37. Adefovir [who-dd]

38. Dsstox_cid_26214

39. Dsstox_rid_81442

40. Dsstox_gsid_46214

41. Schembl49373

42. Chebi:2469

43. Adefovir, >=98% (hplc)

44. Dtxsid6046214

45. Chebi:134512

46. P-[[2-(6-amino-9h-purin-9-yl)ethoxy]methyl]phosphonic Acid

47. 9-[2-phosphonomethoxyethyl]adenine

48. Bcp22955

49. Hy-b1826

50. 9-(2-phosphorylmethoxyethyl)adenine

51. Tox21_111882

52. Ac-012

53. Bdbm50001103

54. S5068

55. Zinc21297308

56. 9-[(2-phosphonylmethoxy)ethyl]adenine

57. Akos005259246

58. Db13868

59. Ks-5018

60. Ncgc00160539-02

61. Ba166179

62. Cas-106941-25-7

63. Cs-0013877

64. Ft-0601785

65. 9-[3-(phosphonomethoxy)ethyl]adenine (pmea)

66. D02768

67. 941a257

68. A801540

69. Q353551

70. Sr-01000945034

71. Q-200594

72. Sr-01000945034-1

73. Pmea, Gs-393, 9-(2-phosphonylmethoxyethyl)adenine

74. [2-(6-amino-purin-9-yl)-ethoxymethyl]-phosphonic Acid

75. ((2-(6-amino-9h-purin-9-yl)ethoxy)-methyl)phosphonic Acid

76. (pmea)[2-(6-amino-purin-9-yl)-ethoxymethyl]-phosphonic Acid

77. [2-(6-amino-purin-9-yl)-ethoxymethyl]-phosphonic Acid(pmea)

78. Hydrogen {[2-(6-amino-9h-purin-9-yl)ethoxy]methyl}phosphonate

79. P-[[2-(6-amino-9h-purin-9-yl)ethoxy]methyl]-phosphonic Acid

80. 5hg

2.4 Create Date

2005-06-24

3 Chemical and Physical Properties

Molecular Formula	C₈H₁₂N₅O₄P
Molecular Weight	273.19 g/mol
XLogP3	-2
Hydrogen Bond Donor Count	3
Hydrogen Bond Acceptor Count	8
Rotatable Bond Count	5
Exact Mass	273.06269088 g/mol
Monoisotopic Mass	273.06269088 g/mol
Topological Polar Surface Area	136 Å²
Heavy Atom Count	18
Formal Charge	0
Complexity	327
Isotope Atom Count	0
Defined Atom Stereocenter Count	0
Undefined Atom Stereocenter Count	0
Defined Bond Stereocenter Count	0
Undefined Bond Stereocenter Count	0
Covalently Bonded Unit Count	1

4 Drug and Medication Information

4.1 Therapeutic Uses

Phosphonic Acids; Adenine/analogs & derivatives; Antiviral Agents; Reverse Transcriptase Inhibitors

National Library of Medicine's Medical Subject Headings online file (MeSH, 2012)

Adefovir 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. /Included in US product label/

US Natl Inst Health; DailyMed. Current Medication Information for HEPSERA (adefovir dipivoxil) tablet (November 2012). Available from, as of November 14, 2012: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=a60adac4-57c2-4089-aefc-1a77a48676fc

For patients 12 to less than 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. /Included in US product label/

This study investigated the efficacy, safety, and pharmacokinetics of adefovir dipivoxil (ADV) in children and adolescents with chronic hepatitis B (CHB). A total of 173 treatment-naive and treatment-experienced children with hepatitis B e antigen (HBeAg)+ CHB were randomized to ADV or placebo. Randomization was stratified by age (2 to <7 years; >7 to <12 years; >12 to <18 years) and prior treatment. Significantly more ADV-treated subjects aged 12 to <18 years achieved the primary efficacy endpoint (serum hepatitis B virus [HBV] DNA <1,000 copies/mL and normal alanine aminotransferase) compared to placebo-treated subjects (23% versus 0%; P = 0.007). In the younger groups, differences between ADV and placebo at the end of blinded treatment were not statistically significant. More ADV-treated subjects had HBeAg seroconversion: 18 of 113 (15.9%) versus three of 57 (5.3%) (but P = 0.051), and more met the combined endpoint of HBeAg seroconversion, HBV DNA <1,000 copies/mL and normal alanine aminotransferase (12/113 versus 0/57; P = 0.009). No subject developed an ADV-associated mutation that has been linked to HBV DNA rebound (that is, mutations rtN236T or rtA181V). ADV plasma concentrations were comparable across groups and within the target range. ADV treatment was well tolerated; no new safety issues were identified. Treatment-related adverse events were reported for 12% of ADV-treated and 10% of placebo-treated subjects. After 48 weeks of ADV treatment, antiviral efficacy in subjects ages 12 to <18 years with HBeAg+ CHB was similar to that observed in a study in adult treatment-naive subjects with HBeAg+ CHB. ADV was not different from placebo in subjects aged 2 to 11 years despite adequate plasma ADV exposure in all three age groups. CONCLUSION: ADV showed significant antiviral efficacy in subjects aged 12 to 17 years with HBeAg+ CHB, but was not different from placebo in subjects aged 2 to 11 years.

PMID:18433023 Jonas MM et al; Hepatology 47 (6): 1863-71 (2008)

4.2 Drug Warning

/BOXED WARNING/ Severe acute exacerbations of hepatitis have been reported in patients who have discontinued anti-Hepatitis B therapy including adefovir. Hepatic function should be monitored closely with both clinical and laboratory follow-up for at least several months in patients who discontinue anti-Hepatitis B therapy. If appropriate, resumption of anti-Hepatitis B therapy may be warranted.

/BOXED WARNING/ In patients at risk of or having underlying renal dysfunction, chronic administration of adefovir may result in nephrotoxicity. These patients should be monitored closely for renal function and may require dose adjustment.

/BOXED WARNING/ HIV resistance may emerge in chronic hepatitis B patients with unrecognized or untreated Human Immunodeficiency Virus (HIV) infection treated with anti-hepatitis B therapies, such as therapy with adefovir, that may have activity against HIV.

Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogs alone or in combination with other antiretrovirals.

For more Drug Warnings (Complete) data for Adefovir (20 total), please visit the HSDB record page.

5 Pharmacology and Biochemistry

5.1 MeSH Pharmacological Classification

Antiviral Agents

Agents used in the prophylaxis or therapy of VIRUS DISEASES. Some of the ways they may act include preventing viral replication by inhibiting viral DNA polymerase; binding to specific cell-surface receptors and inhibiting viral penetration or uncoating; inhibiting viral protein synthesis; or blocking late stages of virus assembly. (See all compounds classified as Antiviral Agents.)

Reverse Transcriptase Inhibitors

Inhibitors of reverse transcriptase (RNA-DIRECTED DNA POLYMERASE), an enzyme that synthesizes DNA on an RNA template. (See all compounds classified as Reverse Transcriptase Inhibitors.)

5.2 FDA Pharmacological Classification

5.2.1 Active Moiety

ADEFOVIR

5.2.2 FDA UNII

6GQP90I798

5.2.3 Pharmacological Classes

Mechanisms of Action [MoA] - Nucleoside Reverse Transcriptase Inhibitors

5.3 Absorption, Distribution and Excretion

Following oral administration of adefovir dipivoxil, approximate bioavailability of adefovir is 59%. A single 10-mg oral dose of adefovir dipivoxil in adults results in peak adefovir plasma concentration within 0.58-4 hours.

American Society of Health-System Pharmacists 2012; Drug Information 2012. Bethesda, MD. 2012, p. 805

4% or less of adefovir is bound to plasma or serum proteins.

American Society of Health-System Pharmacists 2012; Drug Information 2012. Bethesda, MD. 2012, p. 805

In vitro binding of adefovir to human plasma or human serum proteins is less than or equal to 4% over the adefovir concentration range of 0.1 to 25 ug/mL. The volume of distribution at steady-state following intravenous administration of 1.0 or 3.0 mg/kg/day is 392 +/- 75 and 352 +/- 9 mL/kg, respectively.

Food does not affect the area under the concentration-time curve (AUC) of adefovir.

American Society of Health-System Pharmacists 2012; Drug Information 2012. Bethesda, MD. 2012, p. 805

For more Absorption, Distribution and Excretion (Complete) data for Adefovir (10 total), please visit the HSDB record page.

5.4 Metabolism/Metabolites

9-(2-Phosphonylmethoxyethyl)adenine (PMEA) was the only metabolite formed after oral administration of bis-POM PMEA. Three metabolites were detected after oral administration of either bis-(phenyl) PMEA or bis-(o-ethoxyphenyl) PMEA to rats: PMEA, the corresponding monoester, and 2-adenylacetic acid. The major metabolite of bis-(phenyl) PMEA was 2-adenylacetic acid following oral administration. 2-Adenylacetic acid appears to have been formed from the intact prodrugs by a P450 mediated oxidation of the ethyl side chain.

PMID:9172955 Shaw JP et al; Drug Metab Dispos 25 (3): 362-6 (1997)

Following oral administration, adefovir dipivoxil is converted to the active adefovir.

American Society of Health-System Pharmacists 2012; Drug Information 2012. Bethesda, MD. 2012, p. 805

PMEA is a known human metabolite of pradefovir.

S73 | METXBIODB | Metabolite Reaction Database from BioTransformer | DOI:10.5281/zenodo.4056560

5.5 Biological Half-Life

Plasma adefovir concentrations declined in a biexponential manner with a terminal elimination half-life of 7.48 +/- 1.65 hours.

... Diphosphorylated ... PMEA has a relatively long intracellular half-life (16-18 hr) ...

PMID:1705039 Full text: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC51046 Balzarini J et al; Proc Natl Acad Sci (USA) 88 (4): 1499-503 (1991)

5.6 Mechanism of Action

Adefovir dipivoxil is a prodrug of adefovir, an acyclic nucleotide analog antiviral agent. Following initial diester hydrolysis in vivo to form adefovir, the drug undergoes subsequent phosphorylation by cellular enzymes to form its active metabolite, adefovir diphosphate. Adefovir diphosphate inhibits hepatitis B virus (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. Adefovir diphosphate is a weak inhibitor of human DNA polymerases, including alpha- and gamma-polymerases.

American Society of Health-System Pharmacists 2012; Drug Information 2012. Bethesda, MD. 2012, p. 805

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. The inhibition constant (Ki) for adefovir diphosphate for HBV DNA polymerase was 0.1 uM. Adefovir diphosphate is a weak inhibitor of human DNA polymerases alpha and gamma with Ki values of 1.18 uM and 0.97 uM, respectively.

9-(2-Phosphonylmethoxyethyl)adenine (PMEA) is a potent and selective inhibitor of retrovirus (i.e., human immunodeficiency virus) replication in vitro and in vivo. Uptake of PMEA by human MT-4 cells and subsequent conversion to the mono- and diphosphorylated metabolites (PMEAp and PMEApp) are dose-dependent and occur proportionally with the initial extracellular PMEA concentrations. Adenylate kinase is unable to phosphorylate PMEA. However, 5-phosphoribosyl-1-pyrophosphate synthetase directly converts PMEA to PMEApp with a Km of 1.47 mM and a Vmax that is 150-fold lower than the Vmax for AMP. ATPase, 5'-phosphodiesterase, and nucleoside diphosphate kinase are able to dephosphorylate PMEApp to PMEAp, albeit to a much lower extent than the dephosphorylation of ATP. PMEApp has a relatively long intracellular half-life (16-18 hr) and has a much higher affinity for the human immunodeficiency virus-specified reverse transcriptase than for the cellular DNA polymerase alpha (Ki/Km: 0.01 and 0.60, respectively). PMEApp is at least as potent an inhibitor of human immunodeficiency virus reverse transcriptase as 2',3'-dideoxyadenosine 5'-triphosphate. Being an alternative substrate to dATP, PMEApp acts as a potent DNA chain terminator, and this may explain its anti-retrovirus activity.

PMID:1705039 Full text: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC51046 Balzarini J et al; Proc Natl Acad Sci (USA) 88 (4): 1499-503 (1991)

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