147127-20-6 Usage
Description
Tenofovir is an analog of adenosine monophosphate with antiviral activity. It is converted by cellular enzymes to tenofovir diphosphate, an obligate chain terminator that inhibits the activity of HIV reverse transcriptase and hepatitis B virus polymerase. Tenofovir diphosphate is a weak inhibitor of mammalian DNA polymerases α and β and mitochondrial DNA polymerase γ. For in vivo and cell culture use, tenofovir is supplied as a water-soluble prodrug in the form of tenofovir disoproxil (fumarate), which increases the intracellular diphosphorylated compound >1,000-fold above the level attained with unmodified tenofovir. It is a white crystalline solid and a member of the class of phosphonic acids.
Uses
Used in Antiviral Applications:
Tenofovir is used as an anti-HIV agent for the treatment of chronic hepatitis B as well as prevention and treatment of HIV/AIDS. It is a nucleotide analog, acting as a reverse-transcriptase inhibitor (NtRTI). It inhibits the activity of HIV reverse transcriptase through competing with the natural substrate deoxyadenosine 5'-triphosphate, causing the termination of the DNA chain.
Used in Pharmaceutical Industry:
Tenofovir is used as an active pharmaceutical ingredient in combination therapy for the treatment of HIV infection. The bis(isopropyloxycarbonyloxyethyl) ester (disoproxil ester) prodrug is used as the fumaric acid salt, enhancing its efficacy and bioavailability in patients.
Indications and Usage
Tenofovir disoproxil (Viread) is the first nucleotide analogue approved by the American FDA to treat HIV-1 infections. Tenofovir disoproxil is a drug used in the AIDS cocktail treatment method, and research shows that it has the ability to increase monkeys’ immunity to immunodeficiency viruses (similar to the human AIDS virus). Tenofovir disoproxil is used in combination with other reverse transcriptase inhibitors to treat HIV-1 infections and hepatitis B.
Mechanisms of Action
Tenofovir disoproxil is an acyclic nucleoside antivirus drug and has an inhibiting effect on HBV multi-enzyme complexes and HIV reverse transcriptase. Its active content tenofovir phosphonate directly competitively binds to natural deoxyribose substrate to inhibit the virus multi-enzyme complex and inserts itself into the DNA to end the nucleotide chain. Tenofovir disoproxil is barely absorbed by the gastrointestinal duct, so it undergoes esterification and ionization to become tenofovir ester fumarate. Tenofovir is soluble in water and can be quickly absorbed and decomposed into the active substance tenofovir, which then transforms into the active metabolite tenofovir phosphonate. As this drug is not metabolized by the CYP450 enzyme system, it has a very low chance of drug interactions caused by this enzyme.
Pharmacokinetics
Tenofovir disoproxil reaches peak blood concentration 1-2 hours after intake. Tenofovir disoproxil’s bioavailability increases by about 40% when taken with food. The intracellular half-life of tenofovir phosphonate is about 10 hours, so doses can be taken once daily. This drug is mainly filtered through renal glomeruli and excreted through the renal tubule transport system, with 70-80% excreted in its original form through urine.
Pharmacokinetics
Oral absorption: c. 25%
Cmax 300 mg once daily: 0.3 mg/L
Plasma half-life: 17 h
Volume of distribution: 1.3 ± 0.6 L/kg at 3.0 mg/kg
intravenous dose
Plasma protein binding: <0.7% (in vitro)
Absorption and distribution
Oral bioavailability is poor, but is enhanced by administration as the disoproxil prodrug. It may be taken with or without food. CSF penetration is likely to be minimal due to the anionic charge of the molecule at physiological pH. It accumulates in semen at higher concentrations than in plasma. It is not known if it is distributed into breast milk.
Metabolism and excretion
Tenofovir is not metabolized and is principally eliminated by the kidneys by a combination of glomerular filtration and active tubular secretion. In patients with renal dysfunction the dose should be adjusted accordingly.
Compounds such as cidofovir, aciclovir (acyclovir), valaciclovir, ganciclovir, valganciclovir and probenecid may compete for renal excretion. Tenofovir levels are increased when prescribed with some HIV protease inhibitors. The co-administration of tenofovir with didanosine leads to didanosine accumulation which is thought to occur through inhibition of purine nucleoside phosphorylase. This has been associated with impaired immune recovery and several cases of lactic acidosis and pancreatitis. If tenofovir is combined with didanosine the dose of didanosine should be reduced to 200 mg (<60 kg) or 250 mg (≥60 kg) per day and the patient monitored for symptoms of didanosine toxicity.
Adverse Effects
Weakness and exhaustion.
Mild to moderate gastrointestinal reactions, including diarrhea, stomach pain, nausea, vomiting, bloating, lactic acid poisoning, hepatomegaly and fatty liver, and pancreatitis. These adverse reactions also commonly appear individually or combined when taking nucleoside analogues.
Metabolic system hypophosphatemia (1% occurrence rate).
Fat accumulation and redistribution, including centripetal obesity, buffalo hump, thin limbs, breast growth, and Cushing syndrome.
May cause lactic acid poisoning, hepatomegaly related to steatosis, etc.
Effects on nervous system: dizziness and headache.
Effects on respiratory system: difficulty breathing.
Effects on skin: drug rash.
Indications
Tenofovir disoproxil fumarate (Viread) is a prodrug of
tenofovir, a phosphorylated adenosine nucleoside analogue,
and is the only available agent of its class. It is
converted by cellular enzymes to tenofovir diphosphate,
which competes with deoxyadenosine triphosphate
(dATP) for access to reverse transcriptase and
causes chain termination following its incorporation.
Tenofovir was approved as part of a combination therapy
for HIV in adults who failed treatment with other
regimens; it appears to be effective against HIV strains
that are resistant to NRTIs.
Acquired resistance
HIV variants with the K65R mutation and the K70E mutation
in the reverse transcriptase demonstrate reduced susceptibility
to tenofovir.
Pharmaceutical Applications
A nucleotide analog structurally similar to adefovir.
EC50 values for HBV, assessed in the HepG2 2.2.15 cell
line, ranged from 0.14 to 1.5 μm; the cytotoxic concentration
exceeded 100 μm. A decline in HBV DNA levels below
105 copies/mL at 48 weeks of therapy in 100% of patients
receiving tenofovir compared with 44% on adefovir therapy
has been reported. There are also case reports of patients with
primary resistance to adefovir responding to tenofovir.
It is generally well tolerated in patients with chronic HBV;
the most common side effects include nausea and gastrointestinal
upset, headache, dizziness, fatigue and rash.
Pharmaceutical Applications
An acyclic nucleoside phosphonate, formulated as the disoproxil
fumarate salt for oral administration.
Biological Activity
Selectively inhibits HIV reverse transcriptase (RNA-dependent DNA polymerase). Prevents cytotoxicity in SIV-infected C-8166 cells in vitro (IC 50 = 1.5 μ M). Antiviral agent.
Biochem/physiol Actions
Tenofovir has a low oral bioavailability. Hence, it is available as a prodrug called tenofovir disoproxil fumarate. Once ingested, tenofovir disoproxil fumarate is hydrolyzed to tenofovir and phosphorylated. This is then incorporated into the viral DNA which leads to chain termination. Tenofovir is also effective against hepatitis B virus.
Clinical Use
Chronic hepatitis B infection
Side effects
In clinical trials of antiretroviral treatment-naive participants,
the most commonly reported adverse events were mild to
moderate gastrointestinal upset (nausea 8%, diarrhea 11%),
headache (14%) and depression (11%). Tenofovir has the
potential to result in nephrotoxicity, particularly through proximal
tubular damage, but the risk of clinically significant renal
dysfunction appears relatively low and seems to occur mainly
in subjects with other identifiable risks for renal impairment.
Minor elevations in serum creatinine and reductions in creatinine
clearance occur, but rarely require drug discontinuation.
A few (<0.1%) cases of osteomalacia and decreased bone
density have been reported.
Side effects
Tenofovir is taken once daily and is generally well
tolerated, perhaps because it produces less mitochondrial
toxicity than the NRTIs. Nausea, vomiting, flatulence,
and diarrhea occur in 10% or fewer patients.
Resistance to tenofovir has been documented, and
cross-resistance to NRTIs may occur.
Check Digit Verification of cas no
The CAS Registry Mumber 147127-20-6 includes 9 digits separated into 3 groups by hyphens. The first part of the number,starting from the left, has 6 digits, 1,4,7,1,2 and 7 respectively; the second part has 2 digits, 2 and 0 respectively.
Calculate Digit Verification of CAS Registry Number 147127-20:
(8*1)+(7*4)+(6*7)+(5*1)+(4*2)+(3*7)+(2*2)+(1*0)=116
116 % 10 = 6
So 147127-20-6 is a valid CAS Registry Number.
InChI:InChI=1/C9H14N5O4P/c1-6(18-5-19(15,16)17)2-14-4-13-7-8(10)11-3-12-9(7)14/h3-4,6H,2,5H2,1H3,(H2,10,11,12)(H2,15,16,17)/t6-/m0/s1
147127-20-6Relevant articles and documents
Rapid, mild method for phosphonate diester hydrolysis: Development of a one-pot synthesis of tenofovir disoproxil fumarate from tenofovir diethyl ester
Houghton, Stephen R.,Melton, Jack,Fortunak, Joseph,Brown Ripin, David H.,Boddy, Christopher N.
, p. 8137 - 8144 (2010)
A rapid, low temperature hydrolysis of tenofovir diethyl ester mediated by TMSCl and NaBr was identified and demonstrated to be superior to the current production method, TMSBr-mediated hydrolysis. This mild phosphonate ester hydrolysis was then coupled to alkylation of the phosphonic acid, providing a one-pot procedure for formation of tenofovir disoproxil from tenofovir diethyl ester. The hydrolytic conditions developed here dramatically improve the synthesis of tenofovir disoproxyl and will lead to lower cost HIV/AIDS treatment in the developing world.
Di- tert-butyl Phosphonate Route to the Antiviral Drug Tenofovir
Dietz, Jule-Philipp,Ferenc, Dorota,Jamison, Timothy F.,Gupton, B. Frank,Opatz, Till
supporting information, p. 789 - 798 (2021/03/01)
Di-tert-butyl oxymethyl phosphonates were investigated regarding their suitability for preparing the active pharmaceutical ingredient tenofovir (PMPA). First, an efficient and simple access to the crystalline di-tert-butyl(hydroxymethyl)phosphonate was developed. O-Mesylation gave high yields of the active phosphonomethylation reagent. For the synthesis of tenofovir, a two-step sequence was developed using Mg(OtBu)2 as the base for the alkylation of (R)-9-(2-hydroxypropyl)adenine. Subsequent deprotection could be achieved with aqueous acids. (Di-tert-butoxyphosphoryl)methyl methanesulfonate showed to be the most efficient electrophile tested, affording PMPA in 72% yield on a 5 g scale. The developed protocol could also be applied for the preparation of the hepatitis B drug adefovir (64% yield/1 g scale).
Green and environment-friendly preparation method of tenofovir
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Paragraph 0028; 0033, (2020/06/16)
The invention discloses a green and environment-friendly tenofovir preparation method which comprises the following steps: dissolving a compound I, S-propylene carbonate and an inorganic weak base inan organic solvent, reacting for 3-6 hours at 85-120 DEG C, cooling to room temperature, and concentrating an obtained system under reduced pressure to obtain an intermediate II; dissolving the intermediate II, hydroxymethylphosphonic acid dialkyl ester and trialkyl (aryl) phosphine in an organic solvent, stirring at room temperature, slowly adding azodicarboxylic acid diester, and reacting for 20minutes to 3 hours to obtain an intermediate III; slowly adding an inorganic strong alkali into the intermediate III, carrying out ice bath, filtering, adjusting the pH value of an obtained filtrate,standing, carrying out suction filtration, washing an obtained filter cake, and carrying out vacuum drying under reduced pressure. According to the method, S-propylene carbonate, adenine and derivatives thereof are taken as initial raw materials; PMPA is generated through configuration inversion of Mitsunobu reaction, the used organic solvents can be recycled, the generated wastewater is mainly aharmless inorganic salt solution, the cost for further treatment and up-to-standard discharge is low, the method is environmentally friendly, the reaction is easy to control, the safety is high, andthe comprehensive economic benefit is high.
