Adefovir (Trade name: Preveon, Hepsera) is a prescription drug used
for the treatment of chronic infections of hepatitis B virus. It can
be formulated as the pivoxil prodrug adefovir dipivoxil. However, it
shows no effect against HIV-1. As a orally administrated acyclic
nucleotide analog reverse transcriptase inhibitor, it blocking the
reproduction of HBV through inhibiting the reverse transcriptase in
the body. One of its advantages over another anti-HBV drug,
lamivudine is that it is much harder for the virus to develop
resistance to it.
https://www.drugbank.ca/drugs/DB00718
http://en.wikipedia.org/wiki/Adefovir
Adefovir has been used to study its anti-retro viral effect on porcine endogenous retrovirus (PERV) activity.
ChEBI: Adefovir is a member of the class of phosphonic acids that is methylphosphonic acid in which one of the methyl hydrogens has been replaced by a 2-(6-amino-9H-purin-9-yl)ethoxy group. An inhibitor of HIV-1 reverse transcriptase, the bis(t-butoxycarbonyloxymethyl) ester (dipivoxil ester) prodrug is used to treat chronic hepatitis B viral infection. It has a role as a HIV-1 reverse transcriptase inhibitor, a drug metabolite, an antiviral drug, a nephrotoxic agent and a DNA synthesis inhibitor. It is a member of 6-aminopurines, an ether and a member of phosphonic acids. It is functionally related to an adenine. It is a conjugate acid of an adefovir(1-).
It has a lower propensity to induce drug resistance than lamivudine.
Clinical trials of patients receiving 48 weeks of therapy
did not identify any cases of resistance. Longer courses
yield resistant strains of HBV with mutations in the DNA
polymerase gene; other rare variants of resistant strains have
been identified. Lamivudine-resistant strains of HBV retain
susceptibility to adefovir.
Pharmaceutical Applications
A nucleotide analog of adenosine monophosphate, administered
orally as its prodrug, adefovir dipivoxil.
Adefovir is an antiviral drug that after intracellular conversion to adefovir diphosphate inhibits hepatitis B virus (HBV) DNA polymerase (reverse transcriptase).
Oral absorption： c. 60%
Cmax 10 mg/kg oral： 18.4 ng/mL
Plasma half-life： c. 7.5 h.
Volume of distribution： 392 mL/kg
Plasma protein binding： Not known
The prodrug is metabolized to adefovir, which is excreted by the kidneys and therefore requires dose adjustment in patients with impaired renal function. It does not induce cytochrome P450 at standard doses and does not influence the metabolism or plasma concentrations of the other licensed medications used in the treatment of hepatitis B.
Treatment of chronic hepatitis B virus infection in patients >12 years
of age
It is generally well tolerated, with headache, pharyngitis,
abdominal pain and peripheral neuropathy being the most
common side effects. Nephrotoxicity has been observed in
some patients, with those receiving higher doses and longer
courses of therapy at greater risk. Exacerbation of hepatitis
has been reported in patients immediately following discontinuation
of treatment. Most exacerbations occur within 12
weeks of stopping therapy, and elevations of alanine aminotransferase
(ALT) up to 10 times the upper limit of normal
can be observed in over 25% of patients. Lactic acidosis has
been reported in a few patients and is an indication for immediate
discontinuation.
The general procedure for the synthesis of ((2-(6-amino-9H-purin-9-yl)ethoxy)methyl)phosphonic acid from diethyl ((2-(6-amino-9H-purin-9-yl)ethoxy)methyl)phosphonate is as follows: a 10L three-necked flask was fitted with a mechanical stirrer and thermometer. 1.4 kg (4.26 mol) of diethyl ((2-(6-amino-9H-purin-9-yl)ethoxy)methyl)phosphonate (Intermediate III) and 8 L of acetonitrile were sequentially added to the flask, followed by the addition of trimethylmethylsilyl bromide. The reaction mixture was stirred at room temperature for 1 hour and then heated to reflux for 2 hours. Upon completion of the reaction, the solvent was removed by distillation under reduced pressure. To the residue, 5 L of water was added, the mixture was stirred and the pH was adjusted to 3.2-3.4 with 25% sodium hydroxide solution. the mixture was heated to reflux for 2 hr. Upon completion of the reaction, the reaction mixture was cooled to room temperature and filtered. The filter cake was purified by aqueous recrystallization and dried under vacuum at 70 °C for 8 h. 9-(2-phosphomethoxyethyl)adenine was obtained as a white crystalline solid powder with a yield of 1.07 kg, 86.3% yield and melting point of 298-300 °C.
[1] Nucleosides and Nucleotides, 1998, vol. 17, # 8, p. 1445 - 1451
[2] Patent: CN104387421, 2016, B. Location in patent: Paragraph 0032-0034
[3] Patent: CN106317115, 2017, A. Location in patent: Paragraph 0035; 0036; 0039; 0040; 0046; 0047; 0048
[4] Patent: CN106699814, 2017, A. Location in patent: Paragraph 0024-0025
[5] Green Chemistry, 2012, vol. 14, # 8, p. 2282 - 2288
![[[2-(6-Amino-9H-purin-9-yl)ethoxy]methyl]phosphonic acid diethyl ester](/CAS/GIF/116384-53-3.gif)
