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Valacyclovir HCl

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Valacyclovir

ChemSpider 2D Image | Valaciclovir | C13H20N6O4

VALACYCLOVIR

124832-26-4 [RN]
2-[(2-amino-6-hydroxy-9H-purin-9-yl)methoxy]ethyl L-valinate
2-[(2-Amino-6-oxo-1,6-dihydro-9H-purin-9-yl)methoxy]ethyl L-valinate [ACD/IUPAC Name]
2-[(2-Amino-6-oxo-1,6-dihydro-9H-purin-9-yl)methoxy]ethyl-L-valinat [German] [ACD/IUPAC Name]
2-{[(2-amino-6-oxo-1,6-dihydro-9H-purin-9-yl)methyl]oxy}ethyl L-valinate
7106
L-Valinate de 2-[(2-amino-6-oxo-1,6-dihydro-9H-purin-9-yl)méthoxy]éthyle [French] [ACD/IUPAC Name]
L-Valine 2-[(2-amino-1,6-dihydro-6-oxo-9H-purin-9-yl)methoxy]ethyl ester
L-valine ester with 9-[(2-hydroxyethoxy)methyl]guanine
L-Valine, 2-[(2-amino-1,6-dihydro-6-oxo-9H-purin-9-yl)methoxy]ethyl ester [ACD/Index Name]
L-valine, 2-[(2-amino-6-hydroxy-9H-purin-9-yl)methoxy]ethyl ester
MZ1IW7Q79D
Valacyclovir
CAS Registry Number: 124832-26-4
CAS Name: L-Valine 2-[(2-amino-1,6-dihydro-6-oxo-9H-purin-9-yl)methoxy]ethyl ester
Additional Names: L-valine ester with 9-[(2-hydroxyethoxy)methyl]guanine; valaciclovir; ValACV
Molecular Formula: C13H20N6O4
Molecular Weight: 324.34
Percent Composition: C 48.14%, H 6.22%, N 25.91%, O 19.73%
Literature References: L-Valine ester prodrug of acyclovir, q.v. Prepn: T. A. Krenitsky et al., EP 308065; L. M. Beauchamp, US4957924 (1989, 1990 both to Wellcome). Evaluation as prodrug: L. M. Beauchamp et al., Antiviral Chem. Chemother. 3, 157 (1992). Clinical pharmacokinetics: S. Weller et al., Clin. Pharmacol. Ther. 54, 595 (1993). Review of pharmacology and clinical efficacy in herpes virus infections: C. M. Perry, D. Faulds, Drugs 52, 754-772 (1996). Clinical trial to prevent cytomegalovirus disease in renal transplantation: D. Lowance et al., N. Engl. J. Med. 340, 1462 (1999); to prevent transmission of genital herpes: L. Corey et al., ibid. 350, 11 (2004).
Derivative Type: Hydrochloride
CAS Registry Number: 124832-27-5
Manufacturers’ Codes: 256U; BW-256U87; BW-256
Trademarks: Valtrex (GSK)
Properties: Crystalline solid, occurs as hydrate. uv max (water): 252.8 nm (e 8530). Soly in water: 174 mg/ml.
Absorption maximum: uv max (water): 252.8 nm (e 8530)
Therap-Cat: Antiviral.
Keywords: Antiviral; Purines/Pyrimidinones
Valaciclovir is the hydrochloride salt of L-valyl ester of the antiviral drug aciclovir (Zovirax[R]). It was first launched in 1995 by GlaxoSmithKline (GSK) for the oral treatment of recurrent genital herpes, varicella zoster virus (VZV) and herpes simplex virus (HSV) infection in immunocompetent adults.
Valaciclovir was originally developed by GSK and was subsequently licensed to Sigma-Tau and Sanofi (formerly known as sanofi-aventis). In March 2003, GSK and Shionogi signed a letter of intent to copromote both aciclovir and valaciclovir in Japan, where it has been marketed by GSK since 2000.

Valaciclovir, also spelled valacyclovir, is an antiviral medication used to treat outbreaks of herpes simplex or herpes zoster(shingles).[1] It is also used to prevent cytomegalovirus following a kidney transplant in high risk cases.[1] It is taken by mouth.[1]

Common side effects include headache and vomiting.[1] Severe side effects may include kidney problems.[1] Use in pregnancy appears to be safe.[1] It is a prodrug, which works after being converted to aciclovir in a person’s body.[1]

Valaciclovir was patented in 1987 and came into medical use in 1995.[2][3] It is available as a generic medication.[4] A month supply in the United Kingdom costs the NHS about £3 as of 2019.[4] In the United States the wholesale cost of this amount is about US$2.80.[5]In 2016 it was the 168th most prescribed medication in the United States with more than 3 million prescriptions.[6]

Medical uses

Valtrex brand valaciclovir 500mg tablets

Valaciclovir is used for the treatment of HSV and VZV infections, including:[7]

  • Oral and genital herpes simplex (treatment and prevention)
  • Reduction of HSV transmission from people with recurrent infection to uninfected individuals
  • Herpes zoster (shingles): the typical dosage for treatment of herpes is 1,000 mg orally three times a day for seven consecutive days.[8]
  • Prevention of cytomegalovirus following organ transplantation
  • Prevention of herpesviruses in immunocompromised people (such as those undergoing cancer chemotherapy)[9]
  • Chickenpox in children ages 2-18)[10]

It has shown promise as a treatment for infectious mononucleosis[11][12][13] and is preventively administered in suspected cases of herpes B virus exposure.[14]

Valaciclovir is not recommended in Bell’s palsy due to lack of benefit.[15]

Adverse effects

Common adverse drug reactions (≥1% of people) associated with valaciclovir are the same as for aciclovir, its active metabolite. They include: nausea, vomiting, diarrhea and headache. Infrequent adverse effects (0.1–1% of patients) include: agitation, vertigo, confusion, dizziness, edemaarthralgia, sore throat, constipation, abdominal pain, rash, weakness and/or renal impairment. Rare adverse effects (<0.1% of patients) include: coma, seizures, neutropenialeukopenia, tremor, ataxiaencephalopathy, psychotic symptoms, crystalluriaanorexia, fatigue, hepatitisStevens–Johnson syndrometoxic epidermal necrolysis and/or anaphylaxis.[7]

Pharmacology

Valaciclovir belongs to a family of molecules. Valaciclovir is a prodrug, an esterified version of aciclovir that has greater oral bioavailability (about 55%) than aciclovir.[10] It is converted by esterases to the active drug, aciclovir, and the amino acidvaline, via hepatic first-pass metabolismAciclovir is selectively converted into a monophosphate form by viral thymidine kinase, which is more effective (3000 times) in phosphorylation of aciclovir than cellular thymidine kinase. Subsequently, the monophosphate form is further phosphorylated into a disphosphate by cellular guanylate kinase and then into the active triphosphate form, aciclo-GTP, by cellular kinases.[10]

Mechanism of action

Aciclo-GTP, the active triphosphate metabolite of aciclovir, is a very potent inhibitor of viral DNA replication. Aciclo-GTP competitively inhibits and inactivates the viral DNA polymerase.[10] Its monophosphate form also incorporates into the viral DNA, resulting in chain termination. It has also been shown that the viral enzymes cannot remove aciclo-GMP from the chain, which results in inhibition of further activity of DNA polymerase. Aciclo-GTP is fairly rapidly metabolized within the cell, possibly by cellular phosphatases.[16]

Aciclovir is active against most species in the herpesvirus family. In descending order of activity:[17]

The drug is predominantly active against HSV and, to a lesser extent, VZV. It is only of limited efficacy against EBV and CMV. However, valacyclovir has recently been shown to lower or eliminate the presence of the Epstein–Barr virus in subjects afflicted with acute mononucleosis, leading to a significant decrease in the severity of symptoms.[11][12][13] Although it can prevent the establishment of viral latency, acyclovir therapy has not proven effective at eradicating latent viruses in nerve ganglia.[17]

As of 2005, resistance to valaciclovir has not been significant. Mechanisms of resistance in HSV include deficient viral thymidine kinase and mutations to viral thymidine kinase and/or DNA polymerase that alter substrate sensitivity.[18]

It also is used for herpes B virus postexposure prophylaxis.[14]

History

Valaciclovir was patented in 1987 and came into medical use in 1995.[2][3] It is available as a generic medication.[4] A month supply in the United Kingdom costs the NHS about £3 as of 2019.[4] In the United States the wholesale cost of this amount is about US$2.80.[5] In 2019, it was the 168th most prescribed medication in the United States with more than 3 million prescriptions.[6]

Formulations

It is marketed by GlaxoSmithKline under the trade names Valtrex and Zelitrex. Valaciclovir has been available as a generic drug in the U.S. since November 25, 2009.[19]

Valtrex is offered in 500 mg and 1 gram tablets, with the active ingredient valacyclovir hydrochloride. The inactive ingredients include carnauba wax, colloidal silicon dioxide, crospovidoneFD&C Blue No. 2 Lakehypromellosemagnesium stearatemicrocrystalline cellulosepolyethylene glycolpolysorbate 80povidone, and titanium dioxide.[20]

SYN

Acyclovir (I) was coupled with N-Cbz-L-valine (II) in the presence of DCC and DMAP to afford the Cbz-protected valyl ester (III). The N-benzyloxycarbonyl group of (III) was then removed by either hydrogenation over Pd/C or by transfer hydrogenation in the presence of formic acid. AU 8820978; EP 0308065; EP 0596542; JP 1989068373; JP 1991115284; US 4957924; US 5061708

SYN 2

In an alternative procedure, condensation of L-valine (IV) with methyl acetoacetate (V) in the presence of NaOH produced the enamine-protected valine sodium salt (VI). Condensation of (VI) with the tosylate (VII), (prepared from acyclovir (I) and tosyl chloride) afforded ester (VIII). Then, acidic hydrolysis of the enaminoester moiety of (VIII) furnished the target valine ester. Similar procedures were also reported using omega-mesyl and omega-chloro acyclovir.

SYN3

The esterification of acyclovir (I) with N-(tert-butoxycarbonyl)-L-valine (II) by means of EDC, TEA and DMAP in DMF gives the corresponding ester (III) which is finally deprotected by means of HCl in water to afford the target valacyclovir.

Valaciclovir

    • Synonyms:Valacyclovir, BW-256U, 256 U 87
    • ATC:J05AB11
  • Use:antiviral, prodrug of aciclovir
  • Chemical name:l-valine 2-[(2-amino-1,6-dihydro-6-oxo-9H-purin-9-yl)methoxy]ethyl ester
  • Formula:C13H20N6O4
  • MW:324.34 g/mol
  • CAS-RN:124832-26-4
  • InChI Key:HDOVUKNUBWVHOX-QMMMGPOBSA-N
  • InChI:InChI=1S/C13H20N6O4/c1-7(2)8(14)12(21)23-4-3-22-6-19-5-16-9-10(19)17-13(15)18-11(9)20/h5,7-8H,3-4,6,14H2,1-2H3,(H3,15,17,18,20)/t8-/m0/s1

Derivatives

monohydrochloride

  • Formula:C13H20N6O4 • HCl
  • MW:360.80 g/mol
  • CAS-RN:124832-27-5

Substance Classes

Synthesis Path

References

    • US 4 957 924 (Burroughs Wellcome; 18.9.1990; GB-prior. 15.8.1987).
    • EP 308 065 (Wellcome Found. Ltd; appl. 12.8.1988; GB-prior. 15.8.1987, 5.11.1987).
  • combination with lamotrigine:

    • WO 9 505 179 (Wellcome Found. Ltd; appl. 17.8.1994; GB-prior. 18.8.1993).
  • water-dispersible tablets:

    • WO 9 213 527 (Wellcome Found. Ltd; appl. 29.1.1992; GB-prior. 30.1.1991, 22.11.1991, 25.11.1991).
  • medical use for preventing post herpetic neuralgia:

    • GB 2 282 759 (SmithKline Beecham; appl. 14.10.1994; GB-prior. 16.10.1993).

References

  1. Jump up to:a b c d e f g “Valacyclovir Hydrochloride Monograph for Professionals”Drugs.com. American Society of Health-System Pharmacists. Retrieved 17 March 2019.
  2. Jump up to:a b Long, Sarah S.; Pickering, Larry K.; Prober, Charles G. (2012). Principles and Practice of Pediatric Infectious Disease. Elsevier Health Sciences. p. 1502. ISBN 1437727026.
  3. Jump up to:a b Fischer, Jnos; Ganellin, C. Robin (2006). Analogue-based Drug Discovery. John Wiley & Sons. p. 504. ISBN 9783527607495.
  4. Jump up to:a b c d British national formulary : BNF 76 (76 ed.). Pharmaceutical Press. 2018. pp. 625–626. ISBN 9780857113382.
  5. Jump up to:a b “NADAC as of 2019-02-27”Centers for Medicare and Medicaid Services. Retrieved 3 March 2019. Cite error: The named reference “NADAC2019” was defined multiple times with different content (see the help page).
  6. Jump up to:a b “The Top 300 of 2019”clincalc.com. Retrieved 22 December 2018. Cite error: The named reference “:1” was defined multiple times with different content (see the help page).
  7. Jump up to:a b Rossi S, editor. Australian Medicines Handbook 2006. Adelaide: Australian Medicines Handbook; 2006. ISBN 0-9757919-2-3[page needed]
  8. ^ Lille, H. Martina; Wassilew, Sawko W. (2006). “Antiviral therapies of shingles in dermatology”. In Gross, Gerd; Doerr, H.W. (eds.). Herpes zoroster: recent aspects of diagnosis and control. Monographs in virology. 26. Basel (Switzerland): Karger Publishers. p. 124. ISBN 978-3-8055-7982-7. Retrieved January 1, 2012.
  9. ^ Elad S, Zadik Y, Hewson I, et al. (August 2010). “A systematic review of viral infections associated with oral involvement in cancer patients: a spotlight on Herpesviridea”. Support Care Cancer18 (8): 993–1006. doi:10.1007/s00520-010-0900-3PMID 20544224.
  10. Jump up to:a b c d “VALTREX (valacyclovir hydrochloride) Caplets -GSKSource”gsksource.com. Retrieved 2019-08-02.
  11. Jump up to:a b Balfour et al. (December 2005) A controlled trial of valacyclovir in infectious mononucleosis. Presented at the 45th Interscience Conference on Antimicrobial Agents and Chemotherapy, Washington, DC., December 18, 2005. Abstract V1392
  12. Jump up to:a b Simon, Michael W.; Robert G. Deeter; Britt Shahan (March 2003). “The Effect of Valacyclovir and Prednisolone in Reducing Symptoms of EBV Illness In Children: A Double-Blind, Placebo-Controlled Study” (PDF)International Pediatrics18 (3): 164–169.[dead link]
  13. Jump up to:a b Balfour HH, Hokanson KM, Schacherer RM, et al. (May 2007). “A virologic pilot study of valacyclovir in infectious mononucleosis”. Journal of Clinical Virology39 (1): 16–21. doi:10.1016/j.jcv.2007.02.002PMID 17369082.
  14. Jump up to:a b “B Virus—First Aid and Treatment—Herpes B—CDC”. Retrieved June 6, 2015.
  15. ^ Baugh, Reginald F.; Basura, Gregory J.; Ishii, Lisa E.; Schwartz, Seth R.; Drumheller, Caitlin Murray; Burkholder, Rebecca; Deckard, Nathan A.; Dawson, Cindy; Driscoll, Colin (November 2013). “Clinical Practice Guideline: Bell’s Palsy”Otolaryngology–Head and Neck Surgery149 (3_suppl): S1–S27. doi:10.1177/0194599813505967ISSN 0194-5998In summary, antiviral therapy alone (acyclovir or valacyclovir) is not recommended in the treatment of Bell’s palsy due to lack of effectiveness of currently available drugs, unnecessary cost, and the potential for drug-related complications.
  16. ^ http://www.uscnk.us/protein-antibody-elisa/Valaciclovir-%28VCV%29-V511.htm[permanent dead link]
  17. Jump up to:a b O’Brien JJ, Campoli-Richards DM (March 1989). “Acyclovir. An updated review of its antiviral activity, pharmacokinetic properties and therapeutic efficacy”. Drugs37 (3): 233–309. doi:10.2165/00003495-198937030-00002PMID 2653790.
  18. ^ Sweetman, Sean C., ed. (2005). Martindale: the complete drug reference (34th ed.). London: Pharmaceutical Press. ISBN 0-85369-550-4OCLC 56903116.[page needed]
  19. ^ Ahmed, Rumman (November 27, 2009). “Ranbaxy Launches Generic Valtrex in U.S.”The Wall Street Journal. Retrieved January 16, 2010.
  20. ^ “Valtrex Prescribing Information” (PDF)GlaxoSmithKline. September 2008. Retrieved May 7, 2009.

External links

Valaciclovir
Valaciclovir structure.svg
Clinical data
Trade names Valtrex, Zelitrex, others
AHFS/Drugs.com Monograph
MedlinePlus a695010
License data
Pregnancy
category
  • AU: B3
  • US: B (No risk in non-human studies)
Routes of
administration
By mouth
ATC code
Legal status
Legal status
  • AU: S4 (Prescription only)
  • UK: POM (Prescription only)
  • US: ℞-only
  • In general: ℞ (Prescription only)
Pharmacokinetic data
Bioavailability 55%
Protein binding 13–18%
Metabolism Liver (to aciclovir)
Elimination half-life <30 minutes (valaciclovir);
2.5–3.6 hours (aciclovir)
Excretion Kidney 40–50% (aciclovir),
faecal 47% (aciclovir)
Identifiers
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
NIAID ChemDB
CompTox Dashboard (EPA)
ECHA InfoCard 100.114.479 Edit this at Wikidata
Chemical and physical data
Formula C13H20N6O4
Molar mass 324.336 g/mol g·mol−1
3D model (JSmol)

//////////////Valacyclovir HCl,hydrochloride salt of L-valyl ester,  aciclovir, GlaxoSmithKline ,

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DR ANTHONY CRASTO

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DR ANTHONY MELVIN CRASTO Ph.D

DR ANTHONY MELVIN CRASTO Ph.D

DR ANTHONY MELVIN CRASTO, Born in Mumbai in 1964 and graduated from Mumbai University, Completed his Ph.D from ICT, 1991,Matunga, Mumbai, India, in Organic Chemistry, The thesis topic was Synthesis of Novel Pyrethroid Analogues, Currently he is working with GLENMARK PHARMACEUTICALS LTD, Research Centre as Principal Scientist, Process Research (bulk actives) at Mahape, Navi Mumbai, India. Total Industry exp 30 plus yrs, Prior to joining Glenmark, he has worked with major multinationals like Hoechst Marion Roussel, now Sanofi, Searle India Ltd, now RPG lifesciences, etc. He has worked with notable scientists like Dr K Nagarajan, Dr Ralph Stapel, Prof S Seshadri, Dr T.V. Radhakrishnan and Dr B. K. Kulkarni, etc, He did custom synthesis for major multinationals in his career like BASF, Novartis, Sanofi, etc., He has worked in Discovery, Natural products, Bulk drugs, Generics, Intermediates, Fine chemicals, Neutraceuticals, GMP, Scaleups, etc, he is now helping millions, has 9 million plus hits on Google on all Organic chemistry websites. His friends call him Open superstar worlddrugtracker. His New Drug Approvals, Green Chemistry International, All about drugs, Eurekamoments, Organic spectroscopy international, etc in organic chemistry are some most read blogs He has hands on experience in initiation and developing novel routes for drug molecules and implementation them on commercial scale over a 30 year tenure till date Dec 2017, Around 35 plus products in his career. He has good knowledge of IPM, GMP, Regulatory aspects, he has several International patents published worldwide . He has good proficiency in Technology transfer, Spectroscopy, Stereochemistry, Synthesis, Polymorphism etc., He suffered a paralytic stroke/ Acute Transverse mylitis in Dec 2007 and is 90 %Paralysed, He is bound to a wheelchair, this seems to have injected feul in him to help chemists all around the world, he is more active than before and is pushing boundaries, He has 9 million plus hits on Google, 2.5 lakh plus connections on all networking sites, 50 Lakh plus views on dozen plus blogs, He makes himself available to all, contact him on +91 9323115463, email amcrasto@gmail.com, Twitter, @amcrasto , He lives and will die for his family, 90% paralysis cannot kill his soul., Notably he has 19 lakh plus views on New Drug Approvals Blog in 216 countries......https://newdrugapprovals.wordpress.com/ , He appreciates the help he gets from one and all, Friends, Family, Glenmark, Readers, Wellwishers, Doctors, Drug authorities, His Contacts, Physiotherapist, etc

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