36791-04-5 Usage
Antiviral drugs
Ribavirin is a novel non-selective nucleoside class broad-spectrum antiviral drug, belonging to the inosine monophosphate (IMP) dehydrogenase inhibitor. It can participate in the guanine participate in the human body metabolism, interfere with the biosynthesis of guanine, prevent the replication of the virus and has inhibitory effect on a variety of DNA and RNA viruses. Ribavirin has a stronger antiviral effect than amantadine and vidarabine, etc with definite efficacy and small drug side effects. Rare adverse reactions include conjunctivitis and hypotension with the former exhibiting as intraocular foreign body sensation, photophobia, itching, swelling and hematoma and the latter manifested as blurred vision, dizziness, and fatigue. It is used for clinical treatment of viral upper respiratory tract infection, respiratory syncytial virus-induced viral pneumonia and bronchitis, influenza, para-influenza, epidemic encephalris, mumps, chickenpox, shingles, herpes zoster, autumn diarrhea, children early-stage adenovirus pneumonia, acute Lassa fever, rubella, viral pneumonia, genital herpes, herpes simplex virus keratitis, psoriasis, etc with special efficacy. It also have certain efficacy on treating epidemic hemorrhagic fever, hepatitis B, and hepatitis A. Applying this drug in early stage of epidemic hemorrhagic fever can shorten the period, reducing the damage of kidney and vascular and symptoms of poisoning.
Pharmacological effects
1, Ribavirin can be subject to phosphorylation in red blood cells to generate ribavirin monophosphate, diphosphate and triphosphate, wherein the ribavirin monophosphate is the strong inhibitor of the inosine monophosphate dehydrogenase which can inhibit cellular guanylate synthesis, decrease the tri-phosphorylation of the intracellular guanylate triphosphate, and blocking the synthesis of viral nucleic acid.
2, ribavirin triphosphate can inhibit the influenza virus RNA polymerase and interfere with viral replication.
3, ribavirin triphosphate can inhibit the synthesis of viral mRNA 5 'end and transcriptase, thereby inhibiting the DNA and RNA synthesis. It has inhibitory effect on various kinds of viruses (including DNA viruses and RNA viruses). It also has prevention and treatment effect on the influenza, adenovirus pneumonia, hepatitis, herpes, and measles and is also effective on treating the epidemic hemorrhagic fever.
4, it is mainly excreted through urine in the prototype with also a small amount of de-sugarized ribavirin metabolites with a small amount discharged from the feces.
The above information is edited by the lookchem of Dai Xiongfeng.
Chemical Properties
Different sources of media describe the Chemical Properties of 36791-04-5 differently. You can refer to the following data:
1. This product is colorless or white crystalline powder and is odorless with no taste. It is stable in room temperature. It is easily soluble in water and slightly soluble in ethanol, chloroform and ether. It has its mp being 174-176 ℃ or 160-167 ℃ (refined products include two crystals).
2. Colourless Solid
Uses
Different sources of media describe the Uses of 36791-04-5 differently. You can refer to the following data:
1. It is a kind of broad-spectrum antiviral drugs for treating influenza (influenza A and B viruses), adenovirus pneumonia, hepatitis, herpes, measles with prevention and treatment effect; it is also effective on treating the epidemic hemorrhagic fever, particularly effective treatment of patients in their early stages. Oral administration can cause diarrhea without other significant toxicity but may cause neutropenia. Large dose can inhibit the maturation of hemoglobin and red blood cells, causing reversible anemia. There have been reports regarding to the teratogenicity and embryo toxicity in animal experiments. Pregnant women should be hanged.
Ribavirin is a broad-spectrum antiviral nucleoside drug used for treating influenza, adenovirus pneumonia of children, viral hepatitis, respiratory syncytial virus infection, acute keratitis, conjunctivitis, epidemic hemorrhagic fever and herpes zoster.
2. Purine nucleoside analog; inhibits inosine monophosphate dehydrogenase (IMPDH). Used as an antiviral agent.
3. aldosterone antagonist; antifibrogenic
4. anti-infective, anti-fungal
5. A broad spectrum antiviral nucleoside and inhibitor of inosine monophosphate dehydrogenase.
6. Ribavirin is a guanosine analog with antiviral properties against DNA and RNA viruses, including respiratory syncytial virus, hepatitis C, and influenza. It acts as a prodrug that can be activated by either mono- or tri-phosphorylation by cellular kinases. These phosphorylated derivatives of ribavirin have diverse effects on both cellular and viral enzymes, resulting in suppression of viral replication.
Production method
Take nucleotide or nucleoside as the starting material
First hydrolyze the guanosine and guanylate upon the action of glacial acetic acid and acetic anhydride to generate ribose-1-phosphate, which is then subject to the catalysis of double-para-nitro phenol to have reaction with triazide amide to generate condensate with aminolysis to obtain the product.
Guanosine (or guanylate) [acetic anhydride, glacial acetic acid]→[hydrolysis] ribose-1-phosphate [bis-(p-nitrophenol)-phosphate]→[triazide carboxamide] condensates [aminolysis]→Ribavirin
Enzymatic synthesis
First hydrolyze the guanosine and guanosine acid under the action of pyrimidine nucleoside phosphorylase to form ribose-1-phosphate which then, under the action of purine nucleoside phosphorylase, has reaction with triazide amide to directly generate triazole nucleosides.
Guanosine (or guanylate) [pyrimidine nucleoside phosphorylase] → ribose-1 nucleic acid [purine nucleotide cyclase] → Ribavirin.
Description
Ribavirin is a clinically useful antiviral medication for Hepatitis C, viral hemorrhagic fevers and other RNA and DNA viruses. The exact mechanism of its antiviral activity is uncertain. Various proposals include inhibition of viral polymerase1, RNA mutagenesis2, and inosine monophosphate dehydrogenase (IMPDH) inhibition3. Sensitizes tumor cells to anticancer agents 5-fluorouracil5 and doxorubicin6 via inhibition of eIF4E. Displays efficacy against atypical teratoid/rhabdoid tumors7 and inhibits glioma cell growth8.
Definition
ChEBI: A 1-ribosyltriazole that is the 1-ribofuranosyl derivative of 1,2,4-triazole-3-carboxamide. An inhibitor of HCV polymerase.
Indications
Ribavirin is a synthetic guanosine analogue that possesses
broad antiviral inhibitory activity against many
viruses, including influenza A and B, parainfluenza,RSV,
HCV, HIV-1, and various herpesviruses, arenaviruses,
and paramyxoviruses. Its exact mechanism of action has
not been fully elucidated; however, it appears to inhibit
the synthesis of viral mRNA through an effect on nucleotide
pools. Following absorption, host cell enzymes
convert ribavirin to its monophosphate, diphosphate,
and triphosphate forms. Ribavirin monophosphate inhibits the guanosine triphosphate (GTP) synthesis
pathway and subsequently inhibits many GTP-dependent
processes. Ribavirin triphosphate inhibits the 5 capping
of viral mRNA with GTP and specifically inhibits
influenza virus RNA polymerase. Ribavirin may also
act by increasing the mutation rate of RNA viruses, leading
to the production of nonviable progeny virions.
Ribavirin resistance has not been documented in clinical
isolates.
Brand name
Copegus (Roche); Rebetol (Schering); Virazole (Valeant).
Acquired resistance
Development of resistant virus strains has not been
demonstrated.
General Description
Different sources of media describe the General Description of 36791-04-5 differently. You can refer to the following data:
1. White powder. Exists in two polymorphic forms.
2. Ribavirin is 1-β-D-ribofuranosyl-1,2,4-thiazole-3-carboxamide.The compound is a purine nucleoside analog with amodified base and a D-ribose sugar moiety.Ribavirin inhibits the replication of a very wide variety ofRNA and DNA viruses,68 including orthomyxoviruses,paramyxoviruses, arenaviruses, bunyaviruses, herpesviruses,adenoviruses, poxvirus, vaccinia, influenza virus(types A and B), parainfluenza virus, and rhinovirus. In spiteof the broad spectrum of activity of ribavirin, the drug hasbeen approved for only one therapeutic indication—thetreatment of severe lower respiratory infections caused byRSV in carefully selected hospitalized infants and youngchildren.
Air & Water Reactions
Water soluble.
Reactivity Profile
Ribavirin may be sensitive to prolonged exposure to light.
Hazard
Mildly toxic by ingestion. An experimental
teratogen.
Fire Hazard
Flash point data for Ribavirin are not available; however, Ribavirin is probably combustible.
Pharmaceutical Applications
A synthetic nucleoside. It is neither a classic pyrimidine nor a
purine, but stereochemical studies indicate that it is a guanosine
analog. It is usually formulated for administration by inhalation,
but oral and intravenous preparations are also used.
Biochem/physiol Actions
Antiviral agent used against a wide variety of human viral infections, in particular, chronic hepatitis?C, HIV, and adenovirus. Its metabolite, ribavirin 5′-phosphate, is an inhibitor of inosine monophosphate (IMP) dehydrogenase, but many other mechanisms of action are also supported with experimental evidence.
Mechanism of action
Ribavirin, a guanosine analogue, has broad-spectrum antiviral activity against both DNA and RNA viruses. It is phosphorylated by adenosine kinase to the triphosphate, resulting in the inhibition of viral
specific RNA polymerase, disrupting messenger RNA and nucleic acid synthesis.
Pharmacology
Oral and intravenous ribavirin are associated with
additional adverse effects.When given via these routes,
ribavirin can produce hemolytic anemia that is reversible
following dosage reduction or cessation of therapy.
When given in combination with interferon- , ribavirin
increases the incidence of many of its side effects,
such as fatigue, nausea, insomnia, depression, and anemia,
and may cause fatal or nonfatal pancreatitis.
Ribavirin is mutagenic, teratogenic, and embryotoxic in
animals at doses below the therapeutic level in humans.
It is contraindicated in pregnant women and in the male
partners of pregnant women. Women of childbearing
potential and male partners of these women must use
two effective forms of contraception during ribavirin
treatment and for 6 months post therapy. Pregnant
women should not directly care for patients receiving
ribavirin.
Pharmacokinetics
Oral absorption： 36–46%
Cmax 3 mg/kg oral： 4.1–8.2 μmol/L after 1–1.5 h
600 mg intravenous： 43.6 μmol/L end infusion
Plasma half-life： c. 24 h
Volume of distribution： 647 L
Plasma protein binding： <10%
Absorption
It is rapidly absorbed after oral administration. Mean peak concentrations after 1 week of oral doses of 200, 400 and 800 mg every 8 h were 5.0, 11.1 and 20.9 μmol/L, respectively. Trough levels 9–12 h after the end of 2 weeks’ therapy were 5.1, 13.2 and 18.4 μmol/L, respectively, indicating continued accumulation of the drug. Drug was still detectable 4 weeks later. Mean peak plasma concentrations after intravenous doses of 600, 1200 and 2400 mg were 43.6, 72.3 and 160.8 μmol/L, respectively; at 8 h the mean plasma concentrations were 2.1, 5.6 and 10.2 μmol/L. Aerosolized doses (6 g in 300 mL distilled water) are generally administered at a rate of 12–15 mL/h using a Collison jet nebulizer, the estimated dosage being 1.8 mg/kg per h for infants and 0.9 mg/kg per h for adults. When administered by small particle aerosol for 2.5–8 h, plasma concentrations ranged from 0.44 to 8.7 μmol/L.
Metabolism and excretion
It is rapidly degraded by deribosylation or amide hydrolysis, and together with its metabolites is slowly eliminated by the kidney. About 50% of the drug or its metabolites appear in the urine within 72 h and 15% is excreted in the stools. The remainder seems to be retained in body tissues, principally in red blood cells, which concentrate the drug or metabolites to a peak at 4 days, with a half-life of around 40 days. After intravenous administration 19.4% of the dose was eliminated during the first 24 h (compared with 7.3% after an oral dose), the difference reflecting the bioavailability.
Clinical Use
Different sources of media describe the Clinical Use of 36791-04-5 differently. You can refer to the following data:
1. RSV infections in infants (by nebulizer) in emergency situations
(i.e. transplant recipients)
Lassa fever
Hepatitis C (in combination with interferon-α)
Use in RSV pneumonia in infants is no longer routine. It
reduces mortality from Hantaan virus, the agent responsible
for hemorrhagic fever with renal syndrome.
2. Ribavirin aerosol (Virazole) is indicated in the treatment
of high-risk infants and young children with severe
bronchiolitis or pneumonia due to RSV infection.
Treatment is most effective if begun within 3 days of the
onset of symptoms.
Although ribavirin monotherapy is ineffective
against HCV, oral ribavirin in combination with interferon-α
(Rebatron) is approved for this indication and is
effective in patients resistant to interferon therapy
alone. Intravenous ribavirin may be useful in the therapy
of Hantaan virus infection, Crimean or Congo virus
hemorrhagic fever, Lassa fever, and severe adenovirus
infection.
Side effects
Different sources of media describe the Side effects of 36791-04-5 differently. You can refer to the following data:
1. Most adverse effects associated with aerosol ribavirin
are local. Pulmonary function may decline if aerosol ribavirin
is used in adults with chronic obstructive lung disease
or asthma. Deterioration of pulmonary and cardiovascular
function has also been seen in severely ill
infants given this preparation. Rash, conjunctivitis, and
rare cases of anemia have been reported. Health care
workers exposed to aerosol ribavirin during its administration
have reported adverse effects including headache,
conjunctivitis, rash, and rarely, bronchospasm.
2. It is generally well tolerated, though adverse reactions appear
to be related to dose and duration of therapy. Minor adverse
reactions include metallic taste, dry mouth sensation and
increased thirst, flatulence, fatigue and CNS complaints,
including headache, irritability and insomnia. Daily doses of
1 g may cause unconjugated bilirubin levels to double and
the reticulocyte count to increase. Hemoglobin concentrations
may decrease with treatment or higher dosages; with
doses of 3.9–12.6 g per day, a drop in hemoglobin was noted
by days 7–13 of treatment, which was generally ‘rapidly’
reversible
on withdrawal of the drug, but in some instances
necessitated blood transfusion.
Aerosol administration of about 2 g in 36 or 39 h during
3 days is well tolerated, does not affect results of pulmonary
function tests, and seems non-toxic.
It is both teratogenic and embryotoxic in laboratory animals,
so precautions must be observed in women of childbearing
age.
Synthesis
Ribavirin, 1-β-D-ribofuranosyl-1H-1,2,4-triazol-3-carboxamide (36.1.28), is
synthesized by reacting methyl ester of 1,2,4-triazol-3-carboxylic acid with O-1,2,3,
5-tetraacetyl-β-D-ribofuranose to make methyl ester of 1-O-2,3,5-tetraacetyl-β-D-ribofuranosyl-1,2,4-triazol-3-carboxylic acid (36.1.27), which is treated with an ammonia solution
of methanol to simultaneously dezacylate the carbohydrate part and amidation of the carboxyl part of the product to give ribavirin.
Drug interactions
Potentially hazardous interactions with other drugs
Antivirals: effects possibly reduced by abacavir;
increased risk of toxicity with stavudine; increased
side effects with didanosine - avoid; increased risk of
anaemia with zidovudine - avoid.
Azathioprine: possibly enhances myelosuppressive
effects of azathioprine.
Metabolism
Ribavirin is metabolised by reversible phosphorylation
and a degradative pathway involving deribosylation and
amide hydrolysis to produce an active triazole carboxyacid
metabolite.
Ribavirin is mainly excreted in the urine as unchanged
drug and metabolites.
References
1) Bougie and Bisaillon (2003), Initial binding of the broad spectrum antiviral nucleoside ribavirin to the hepatitis C virus RNA polymerase; J. Biol. Chem. 278 52471
2) Crotty et al. (2000), The broad-spectrum antiviral ribonucleoside ribavirin is an RNA virus mutagen; Nat. Med. 6 1375
3) Zhou et al. (2003), The effect of ribavirin and IMPDH inhibitors on hepatitis C virus subgenomic replicon RNA; Virology 310 333
4) Couee and Tipton (1990), Inhibition of ox brain glutamate by perphenazine; Biochem. Pharmacol. 39 1167
5) Hu et al. (2019), Ribavirin sensitizes nasopharyngeal carcinoma to 5-fluorouracil through suppressing 5-fluorouracil-induced ERK-dependent-elF4E activation; Biochem. Biophys. Res. Commun. 513 862
6) Tan et al. (2018), Ribavirin augments doxorubicin’s efficacy in human hepatocellular carcinoma through inhibiting doxorubicin-induced elF4E activation; J. Biochem. Mol. Toxicol. 32(1) e22007
7) Casaos et al. (2018), Ribavirin as a potential therapeutic for atypical teratoid/rhabdoid tumors; Oncotarget; 9 8054
8) Volpin et al. (2017) Use of an anti-viral drug, Ribavirin, as an anti-glioblastoma therapeutic; Oncogene, 36 3037
Check Digit Verification of cas no
The CAS Registry Mumber 36791-04-5 includes 8 digits separated into 3 groups by hyphens. The first part of the number,starting from the left, has 5 digits, 3,6,7,9 and 1 respectively; the second part has 2 digits, 0 and 4 respectively.
Calculate Digit Verification of CAS Registry Number 36791-04:
(7*3)+(6*6)+(5*7)+(4*9)+(3*1)+(2*0)+(1*4)=135
135 % 10 = 5
So 36791-04-5 is a valid CAS Registry Number.
InChI:InChI=1/C8H12N4O5/c9-6(16)7-10-2-12(11-7)8-5(15)4(14)3(1-13)17-8/h2-5,8,13-15H,1H2,(H2,9,16)
36791-04-5Relevant articles and documents
Development of a nanostabilized biocatalyst using an extremophilic microorganism for ribavirin biosynthesis
De Benedetti, Eliana C.,Rivero, Cintia W.,Trelles, Jorge A.
, p. 90 - 95 (2015)
Ribavirin is a guanosine analogue commonly used as an antiviral compound for the treatment of Hepatitis C virus (HCV) infection. The biosynthesis of this compound using Geobacillus kaustophilus ATCC 8005 as biocatalyst is herein reported. This extremophilic microorganism has been successfully entrapped in an agarose matrix supplemented with bentonite, which was defined as bionanocomposite. This immobilized biocatalyst was stable for more than 580 h without activity loss, significantly improving operational stability and mechanical properties over the conventional agarose matrix. Furthermore, a packed-bed bioreactor for bioprocess scale-up was designed, which was able to produce 370 mg L-1 of ribavirin. In conclusion, a smooth, inexpensive and environmentally friendly method to obtain ribavirin was developed in this study.
Ribavirin: Biotechnological synthesis and effect on the reproduction of Vaccinia virus
Konstantinova,Leont'eva,Galegov,Ryzhova,Chuvikovskii,Antonov,Esipov,Taran,Verevkina,Feofanov,Miroshnikov
, p. 553 - 560 (2004)
The biotechnological method of synthesis of ribavirin, vidarabin, and 6-azauridine by the use of immobilized recombinant enzymatic preparations of nucleoside phosphorylase was improved. The effect of ribavirin and its combinations with the other synthesized nucleosides on the reproduction of Vaccinia virus was studied on the culture of Vero cells. The combination of ribavirin and vidarabin was shown to provide the antiviral effect at lesser concentrations than with these compounds taken separately.
Purification and properties of purine nucleoside phosphorylase from Brevibacterium acetylicum ATCC 954.
Shirae,Yokozeki
, p. 493 - 499 (1991)
Purine nucleoside phosphorylase of Brevibacterium acetylicum ATCC 954, which catalyzes the production of ribavirin (1-beta-D-ribofuranosyl-1,2,4-triazole-3-carboxamide), a potent antiviral agent, from purine nucleoside and 1,2,4-triazole-3-carboxamide in a high yield, was purified 49-fold. This enzyme had a molecular weight of 31,000 and was a monomer. The isoelectric point of the enzyme was 4.7. The optimal temperature and pH of inosine phosphorolyzing reaction catalyzed by the enzyme was around 8.5 and 70 degrees C, respectively. The Michaelis constants for inosine, guanosine, and ribavirin were 1.43 mM, 2.44 mM and 2.08 mM, respectively, at 40 degrees C. This enzyme appeared to be a SH enzyme because it was inactivated by SH reagents, p-chloromercuribenzoate and N-ethylmaleimide, and HgCl2. In addition, this enzyme was completely inactivated by AgNO3 and was slightly inhibited by CuSO4. It showed nucleoside-phosphorolyzing activity toward inosine, 2'-deoxyinosine, 2',3'-dideoxyinosine, guanosine, 2'-deoxyguanosine, and xanthosine. However, adenosine and its derivatives could not be phosphorolyzed. This enzyme could not also phosphorolyze various 5'-mononucleotides. According to the amino terminal sequence analysis, the twenty residues from the amino terminal end of this enzyme were identified as follows: MTVNWNETRS-FLECKMQAKPE.
A universal biocatalyst for the preparation of base- and sugar-modified nucleosides via an enzymatic transglycosylation
Barai, Vladimir N.,Zinchenko, Anatoli I.,Eroshevskaya, Ludmilla A.,Kalinichenko, Elena N.,Kulak, Tamara I.,Mikhailopulo, Igor A.
, p. 1901 - 1908 (2002)
The E. coli BMT-4D/1A cells have been selected according to Munch-Petersen et al. They carry two regulatory mutations (cytR and deoR) and are able to synthesize constitutively nucleoside-catabolizing enzymes, e.g., cells that possess high UPase and PNPase activities. The cells have been cross-linked by glutaraldehyde to afford a biocatalyst that retained high UPase and PNPase activities and was comfortable for repeated use. An incubation of 2′-deoxyguanosine (1) and 2-chloroadenine (2) (molar ratio 3:1) in K-phosphate buffer (10 mM; pH 7.0) in the presence of the biocatalyst at 65° for 7 h resulted in quantitative transformation of 2 into 2-chloro-2′-deoxyadenosine (4; cladribine) that was isolated in 81% yield (Scheme 1). Similarly, the reaction of guanosine (5) and 1,2,4-triazole-3-carboxamide (6) (molar ratio 1:1) in K-phosphate buffer (10mM; pH 7.0) in the presence of the biocatalyst at 60° for 30h led to the formation of 1-(β-D-ribofuranosyl)-1,2,4-triazole-3-carboxamide (8; ribavirin) in 90-92% yield (67-70% isolated yield) (Scheme 2).
Ribavirin compound containing one-twentieth water
-
Paragraph 0047; 0052; 0053, (2019/01/23)
The invention discloses a ribavirin compound containing one-twentieth water. Each mole of the ribavirin compound contains one-twentieth mole of water. After a crude ribavirin product is dissolved in water, the temperature and pH of a solution are controlled, and crystallization is carried out in an acetonitrile aqueous solvent to obtain the ribavirin compound containing one-twentieth water. The prepared product has high purity and stability and a higher application value.
Ribavirin preparation method
-
Paragraph 0038; 0040; 0044; 0046; 0047; 0049; 0050; 0052, (2019/02/27)
The invention provides a Ribavirin preparation method and belongs to the technical field of pharmaceutical synthesis. The method comprises following steps: tetraacetylribose and methyl triazole carboxylate are subjected to a condensation reaction under catalysis of iodine firstly, a Ribavirin intermediate is obtained and subjected to an ammonolysis reaction, and Ribavirin is obtained. Yield and purity of the Ribavirin intermediate obtained with the method are higher, the yield of the Ribavirin intermediate is 80%-82%, and the purity is 98.5%-98.7%; total yield and purity of the finally prepared Ribavirin are higher, the total yield is 77.6%-79.5%, and the purity is 98.5%.
