113852-37-2 Usage
Description
Cidofovir, also known as (S)-3-hydroxy-2-phosphonomethoxypropyl cytosine (HPMPC, Vistide), is an acyclonucleotide analog with broad-spectrum activity against several DNA viruses. It is a phosphonic acid derivative that does not require viral thymidine kinase phosphorylation to act, making it effective against herpes simplex infections with deficient or altered thymidine kinase activity. Cidofovir is rapidly converted to its active form, cidofovir diphosphate, which inhibits viral DNA polymerase at concentrations significantly lower than that required for human DNA polymerase. It is a competitive inhibitor of dCTP incorporation and can be incorporated into the growing viral DNA strand, causing DNA chain termination. Cidofovir has a high therapeutic index against CMV and has been approved for treating CMV retinitis in patients with AIDS.
Uses
Used in Antiviral Treatment:
Cidofovir is used as an injectable antiviral medication for the treatment of cytomegalovirus (CMV) retinitis in patients with AIDS. It suppresses CMV replication by selective inhibition of viral DNA polymerase, preventing viral replication and transcription.
Used in the Treatment of Acyclovir-Resistant Herpes:
Cidofovir is used as an antiviral agent for the treatment of acyclovir-resistant herpes infections in immunocompromised hosts. It is administered intravenously at a dose of 5 mg/kg/week.
Used in Intralesional Therapy for Papillomatosis:
Cidofovir is used as a complementary intralesional therapy against papillomatosis caused by human papillomavirus (HPV).
Used in the Treatment of Other DNA Virus Infections:
Cidofovir possesses potent activity against a broad spectrum of DNA viruses, such as herpes simplex virus 1 (HSV-1), herpes simplex virus 2 (HSV-2), adenovirus, and papillomavirus. It can be synthesized by various methods, with the most efficient involving ring-opening of (R)-glycidol with cytosine.
General Information:
Cidofovir is administered by slow, constant intravenous infusion in a dose of 5 mg/kg over a 1-hour period once a week for 2 weeks, followed by a maintenance dose every 2 weeks. It has three intracellular metabolites that are also active, resulting in a long half-life and lower dosing times. This allows for the protection of previously uninfected cells from subsequent infection. The brand name for Cidofovir is Vistide, manufactured by Gilead Sciences.
Originator
Gilead Sciences (USA)
Indications
Cidofovir (Vistide) is an acyclic phosphonate cytosine
analogue with activity against herpesviruses including
CMV, HSV-1, HSV-2, EBV, and VZV. It also inhibits
adenoviruses, papillomaviruses, polyomaviruses, and
poxviruses. Activation of cidofovir requires metabolism
to a diphosphate by host cellular enzymes. Because this
activation does not depend upon viral enzymes, similar
levels of cidofovir diphosphate are seen in infected and
uninfected cells. Cidofovir diphosphate competes with
deoxycytidine triphosphate (dCTP) for access to viral DNA polymerase and also acts as an alternative substrate.
The incorporation of one cidofovir molecule into
the growing DNA chain slows replication; sequential incorporation
of two molecules halts DNA polymerase
activity.
Manufacturing Process
By the alkylation of N-benzoyl uracil with the chiral 2-trityloxy-oxirane was
obtained glycoside-like derivative N-[1-(2-hydroxy-3-trityloxy-propyl)-2-oxo-
1,2-dihydroxypyrimidin-4-yl]-N-methylbenzamide as a single isomer. From N-
[1-(2-hydroxy-3-trityloxy-propyl)-2-oxo-1,2-dihydroxypyrimidin-4-yl]-Nmethylbenzamide and toluene-(4-sulfomethyl)phosphonic acid diethyl ester
was prepared [2-[(benzoylmethylamino)-2-oxo-2H-pyrimidin-1-yl]-1-
trityloxymethylethoxymethyl]phosphonic acid diethyl ester. As a result oftreatment of the product with hydrogen chloride was synthesized [2-
[(benzoylmethylamino)-2-oxo-2H-pyrimidin-1-yl]-1-hydroxymethylethoxymethyl]phosphonic acid diethyl ester. Sequential reaction with trimethylsilyl
bromide and ammonium hydroxide cleaves the phosphite ethyl groups and
saponifies the benzamide function to afford (1S)-1-(3-hydroxy-2-
phosphonylmethoxypropyl)cytosine (Cidofovir).
Therapeutic Function
Antiviral
Antimicrobial activity
The phosphonate group enables it to mimic a nucleotide and
bypass virus-dependent phosphorylation. Cellular enzymes
convert it to the triphosphate, which has in-vitro and in-vivo
activity against CMV and other herpesviruses, including aciclovir-
resistant HSV. Oral hairy leukoplakia resolved on therapy,
suggesting that it has activity against EBV. Activity against
adenovirus and papillomaviruses is also reported.
Hazard
A severe skin irritant.
Pharmaceutical Applications
An acyclic cytosine analog administered by intravenous
infusion.
Biochem/physiol Actions
Selective inhibitor of viral DNA synthesis through the selective inhibition of viral DNA polymerase.
Mechanism of action
Cidofovir is a synthetic acyclic pyrimidine nucleotide analogue of cytosine. It is a phosphorylated
nucleotide that is additionally phosphorylated by host cell enzymes to its active intracellular metabolite,
cidofovir diphosphate. This reaction occurs without initial virus-dependent phosphorylation by viral
nucleoside kinases. It has antiviral effects by interfering with DNA synthesis and inhibiting viral
replication.
Pharmacokinetics
Oral absorption: <5%
Cmax 3 mg/kg intravenous infusion: 7.7 mg/L end infusion
10 mg/kg intravenous infusion: 23 mg/L end infusion
Plasma half-life: c. 3–4 h
Volume of distribution: c. 0.6 L/kg
Plasma protein binding: <6%
The intracellular half-life of the diphosphate is 17–65 h. It
is excreted unchanged by the kidney by glomerular filtration
and tubular secretion.
Clinical Use
Treatment of CMV retinitis
Because of nephrotoxicity it is a drug of last resort. It has been
used experimentally in the treatment of adenovirus pneumonia
and BK virus in transplant patients and juvenile laryngeal
papillomatosis.
Clinical Use
Cidofovir is approved for the treatment and prophylaxis
of CMV retinitis in AIDS patients. It has also been
used in the treatment of acyclovir-resistant (viral thymidine
kinase-deficient) HSV infections, polyomavirusassociated
progressive multifocal leukoencephalopathy,
condylomata acuminata (anogenital warts), and molluscum
contagiosum.
Side effects
The most immediately serious adverse effect associated
with cidofovir therapy is nephrotoxicity. Accumulation
of the drug within the proximal tubule epithelial cells
can lead to proteinuria, azotemia, glycosuria, elevated
serum creatinine, and rarely, Fanconi’s syndrome.
Probenecid is administered along with cidofovir to
block its uptake into the proximal tubule epithelial cells
and thereby inhibit its tubular secretion as well as its
toxicity. Probenecid carries its own adverse effects, including
gastrointestinal upset, hypersensitivity reactions,
and a decrease in the elimination of drugs that
also undergo active tubular secretion (e.g. nonsteroidal
antiinflammatory drugs [NSAIDs], penicillin, acyclovir,
zidovudine).Anterior uveitis and neutropenia are fairly common
side effects of cidofovir therapy. Ocular hypotony and
metabolic acidosis are rare. Exposure to therapeutic
levels of cidofovir causes cancer in rats; therefore, this
drug should be considered a potential human carcinogen.
Animal studies have also shown cidofovir to produce
embryotoxic and teratogenic effects and to impair
fertility.
Side effects
Nephrotoxicity, heralded by proteinuria, occurred at weekly
doses of ≤3 mg/kg in two of five patients after 6 and 14 consecutive
weeks of therapy. Two of five patients given 10 mg/kg
developed nephrotoxicity, manifested as a Fanconi-like syndrome,
after only two doses. Biopsy revealed proximal tubular
effects. Prehydration and extended dosing intervals seem to
be nephroprotective.
Drug interactions
Potentially hazardous interactions with other drugs
Antivirals: avoid concomitant use with tenofovir.
Metabolism
After IV doses of cidofovir, serum concentrations decline
with a reported terminal half-life of about 2.2 hours (the
intracellular half-life of the active diphosphate may be up
to 65 hours).Cidofovir is eliminated mainly by renal excretion, both
by glomerular filtration and tubular secretion. About
80-100% of a dose is recovered unchanged from the urine
within 24 hours. Use with probenecid may reduce the
excretion of cidofovir to some extent by blocking tubular
secretion, although 70-85% has still been reported to be
excreted unchanged in the urine within 24 hours.
Check Digit Verification of cas no
The CAS Registry Mumber 113852-37-2 includes 9 digits separated into 3 groups by hyphens. The first part of the number,starting from the left, has 6 digits, 1,1,3,8,5 and 2 respectively; the second part has 2 digits, 3 and 7 respectively.
Calculate Digit Verification of CAS Registry Number 113852-37:
(8*1)+(7*1)+(6*3)+(5*8)+(4*5)+(3*2)+(2*3)+(1*7)=112
112 % 10 = 2
So 113852-37-2 is a valid CAS Registry Number.
InChI:InChI=1/C8H14N3O6P/c9-7-1-2-11(8(13)10-7)3-6(4-12)17-5-18(14,15)16/h1-2,6,12H,3-5H2,(H2,9,10,13)(H2,14,15,16)
113852-37-2Relevant articles and documents
A Practical Synthesis of (S)-HPMPC
Brodfuehrer, Paul R.,Howell, Henry G.,Sapino, Chester Jr.,Vemishetti, Purushotham
, p. 3243 - 3246 (1994)
Synthesis of the title nucleotide was accomplished in high yield starting from (S)-tritylglycidol (5) and N-benzoylcytosine (9).
EGFR inhibitor and antiviral agent for simultaneous, separate or sequential use in the treatment and/or prevention and/or palliation of cancer
-
, (2011/10/13)
The application relates to a combination of biologically active compounds comprising at least one antiviral agent and at least one EGFR antagonist, for simultaneous, separate or sequential use in the treatment and/or prevention and/or palliation of malignant or pre-malignant neoplasms, preferably of solid malignant or pre-malignant neoplasms.
CIDOFOVIR PEPTIDE CONJUGATES AS PRODRUGS
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Page/Page column 11; figure 3, (2008/06/13)
Cidofovir-based compounds having an amino acid, dipeptide or tripeptide attached to a cidofovir or cyclic cidofovir framework. The compounds show enhanced oral bioavailability and increased binding to the PepT1 transporter. The present invention also provides compositions and methods for treating virus infections, and a method of preparing cidofovir.