Cidofovir Chemical Properties

Melting point:

260° (dec)

alpha 

D20 -97.3° (c = 0.80 in water)

Boiling point:

609.5±65.0 °C(Predicted)

Density 

1.76±0.1 g/cm3(Predicted)

storage temp. 

Keep in dark place,Sealed in dry,Store in freezer, under -20°C

solubility 

deionized water: ≥5mg/mL (warmed)

form 

powder

pka

2.29±0.10(Predicted)

Water Solubility 

Soluble to 12 mg/mL (42.98 mM) in Water

InChI

InChI=1S/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)/t6-/m0/s1

InChIKey

VWFCHDSQECPREK-LURJTMIESA-N

SMILES

P(CO[C@H](CO)CN1C(=O)N=C(N)C=C1)(=O)(O)O

CAS DataBase Reference

113852-37-2(CAS DataBase Reference)

Safety Information

Hazard Codes 

T

Risk Statements 

25-38

Safety Statements 

36-37-45

RIDADR 

UN 2811 6.1 / PGIII

WGK Germany 

3

RTECS 

SZ6545000

Hazardous Substances Data

113852-37-2(Hazardous Substances Data)

MSDS

• Language:English Provider:[1-(4-Amino-2-oxo-pyrimidin-1-yl)-3-hydroxy-propan-2-yl]oxymethylphosphonic acid

Cidofovir Usage And Synthesis

Description

Cidofovir launched as a first-line treatment for CMV retinitis in AIDS patients. It is a nucleotide analog with potent activity against a broad spectrum of DNA viruses, e.g., HSVl, HSV2, CMV, adenovirus and papillomavirus. Cidofovir can be synthesized by a number of methods, the most efficient involves ring openning of (R)-glycidol with cytosine. Metabolically, cidofovir does not require intracellular activation by virally-encoded enzymes like similar compounds, e.g., aciclovir or ganciclovir. It is rapidly converted to its active form, cidofovir diphosphate, which inhibits viral DNA polymerase at concentrations up to 600 fold lower than that required for human DNA polymerase. It is a competitive inhibitor of dCTP incorporation or if incorporated into viral DNA slows down further DNA synthesis and causes the destabilization of the viral DNA. There are three intracellular metabolites which are also active thus giving rise to the long half-life. This results in lower dosing times (once every 1-2 weeks) and the ability to protect previously uninfected cells from subsequent infection.

Originator

Gilead Sciences (USA)

Uses

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 and therefore prevention of viral replication and transcription. It is used in the treatment of acyclovir resistant herpes as well as a complementary intralesional therapy against papillomatosis caused by human papillomavirus (HPV).

Uses

Cidofovir suppresses virus replication by selective inhibition of viral DNA synthesis.

Cidofovir, a monophosphorylated nucleotide analog, does not require viral thymidine kinase phosphorylation to act and therefore has activity against herpes simplex infections with deficient or altered thymidine kinase activity. It is ineffective against rare strains with mutations in DNA polymerase. It is administered intravenously, 5 mg/kg/week for acyclovir-resistant infections in immunocompromised hosts. Associated side effects include nephrotoxicity and neutropenia. Concomitant administration of cidofovir with probenecid and saline hydration decreases the nephrotoxicity. Cidofovir resistance has not been documented.

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.

Definition

ChEBI: Cytosine substituted at the 1 position by a 3-hydroxy-2-(phosphonomethoxy)propyl group (S configuration). A nucleoside analogue, it is an injectable antiviral used for the treatment of cytomegalovirus (CMV) retinitis in AIDS patients.

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 of
treatment 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).

brand name

Vistide (Gilead Sciences).

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.

General Description

Cidofovir, (S)-3-hydroxy-2-phosphonomethoxypropyl cytosine(HPMPC, Vistide), is an acyclonucleotide analog thatpossesses broad-spectrum activity against several DNAviruses. Unlike other nucleotide analogs that are activated tonucleoside phosphates, Cidofovir is a phosphonic acid derivative.The phosphonic acid is not hydrolyzed by phosphatasesin vivo but is phosphorylated by cellular kinases to yield adiphosphate. The diphosphate acts as an antimetabolite to deoxycytosinetriphosphate (dCTP). Cidofovir diphosphate is acompetitive inhibitor of viral DNA polymerase and can beincorporated into the growing viral DNA strand, causingDNA chain termination.
Cidofovir possesses a high therapeutic index against CMVand has been approved for treating CMV retinitis in patientswith AIDS. Cidofovir is administered by slow, constant intravenousinfusion in a dose of 5 mg/kg over a 1-hour periodonce a week for 2 weeks. This treatment is followed by amaintenance dose every 2 weeks.

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%
C_max 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.

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