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SYNTHESIS OOFF AANNTTII--VVIIRRAALL 
AAGGEENNTTSS 
DR ANTHONY MELVIN CRASTO 
Ph.D 
2014 
PRINCIPAL SCIENTIST 
PROCESS RESE...
This iiss aa vvaasstt ttooppiicc aanndd aa sshhoorrtt 
oovveerrvviieeww iiss ggiivveenn 
aanndd 
iinn nnoo wwaayy ccoommpp...
DDeeddiiccaatteedd ttoo mmyy ssoonn LLiioonneell 
CCrraassttoo,, 
He was only in first standard in school (dec2007) when 
...
AANNTTII--VVIIRRAALL AAGGEENNTTSS 
VIRUSES: 
Single or double stranded DNA or RNA 
enclosed in a protein – CAPSID 
Oblig...
VVIIRRAALL RREEPPLLIICCAATTIIOONN 
 Viral attachment and entry (enfuvirtide, docosanol, 
palivizumab) 
 Adsorption and p...
AANNTTII--VVIIRRAALL AAGGEENNTTSS 
Anti-Herpes 
Acyclovir Famciclovir Valacyclovir 
Ganciclovir Valganciclovir Lamivudine ...
Anti-retroviral Agents 
Nucleoside RT inhibitors. 
Zidovudine Zalcitabine Didanosine 
Stavudine Lamivudine Abacavir 
Emtri...
AANNTTII--HHeeppaattiittiiss BB 
Lamivudine 
Adenofovir Dipivoxil 
Entecavir 
Interferon alfa-2b 
Famciclovir 
ANTI-H...
PPrrootteeaassee IInnhhiibbiittoorrss 
Saquinavir Lopinavir/Ritonavir 
Indinavir Nelfinavir Amprenavir 
Darunavir Atazanav...
AAnnttii--iinnfflluueennzzaa AAggeennttss 
Amantadine Rimantadine 
Neuraminidase Inhibitors 
Oseltamivir (Tamiflu) 
Zanami...
MMiisscceellllaanneeoouuss 
Immuno-modulating Agents 
Inosiplex Isoprinosine 
Foscarnet
AANNTTII--HHEERRPPEESS 
AANNTTII--VVAARRIICCEELLLLAA ZZOOSSTTEERR
AACCYYCCLLOOVVIIRR 
2-Amino-1,9-dihydro-9-((2-hydroxyethoxy)methyl)-6H-Purin- 
6-one 
Acyclovir(9-[2-hydroxy methyl]-9-H-g...
Title: Acyclovir 
CAS Registry Number: 59277-89-3 
CAS Name: 2-Amino-1,9-dihydro-9-[(2-hydroxyethoxy)methyl]-6H-purin-6-on...
Structures of guanosine and acyclovir compared
SSYYNNTTHHEESSISS
DDeessccrriippttiioonn 
The reaction of benzonitrile (I) with refluxing ethylene glycol (II) gives ethylene glycol 
monobe...
TTHHEERRAAPPEEUUTTIICC UUSSEESS 
ACUTE HERPES ZOSTER (SHINGLES) 
SYSTEMIC ACYCLOVIR PROPHYLAXIS 
HSV ENCEPHALITIS ( IV ...
VVAALLAACCYYCCLLOOVVIIRR 
(S)-2-[(2-amino-6-oxo-6,9-dihydro-3H-purin-9-yl)methoxy]ethyl-2-amino-3- 
methylbutanoate 
 L- ...
Title: Valacyclovir 
CAS Registry Number: 124832-26-4 
CAS Name: L-Valine 2-[(2-amino-1,6-dihydro-6-oxo-9H-purin-9-yl)meth...
SSYYNNTTHHEESSISS
DDEESSCCRRIPPTTIOONN 
Acyclovir (I) was coupled with N-Cbz-L-valine (II) in the 
presence of DCC and DMAP to afford the Cb...
FFAAMMCCIICCLLOOVVIIRR 
2-[(acetyloxy)methyl]-4-(2-amino-9H-purin-9-yl)butyl acetate 
 Diacetyl ester prodrug of 6 deoxy ...
Title: Famciclovir 
CAS Registry Number: 104227-87-4 
CAS Name: 2-[2-(2-Amino-9H-purin-9-yl)ethyl]-1,3-propanediol diaceta...
FFAAMMCCIICCLLOOVVIIRR 
First episode genital herpes 
250 mg TID for 5-10 days 
Recurrent genital herpes – 250 mg BID for ...
DDEESSCCRRIIPPTTIIOONN 
Synthesis 
This compound has been obtained by two similar ways (Scheme 10704402a): 1) 
The reactio...
FFAAMMCCIICCLLOOVVIIRR 
Comparable to valacyclovir in treating 
zoster and reducing associated pain in 
older adults 
50...
PPEENNCCIICCLLOOVVIIRR 
2-amino-9-[4-hydroxy-3-(hydroxymethyl)butyl]-6,9-dihydro-3H-purin- 
6-one 
Penciclovir (9-[4-hydro...
Title: Penciclovir 
CAS Registry Number: 39809-25-1 
CAS Name: 2-Amino-1,9-dihydro-9-[4-hydroxy-3-(hydroxymethyl)butyl]-6H...
PPEENNIICCIICCLLOOVVIIRR 
Penciclovir (INN) is a guanine analogue antiviral drug used for the treatment of 
various herpes...
SSYYNNTTHHEESSIISS
DDEESSCCRRIIPPTTIIOONN 
The synthesis of penciclovir by two related ways has been reported: 1) The reaction of 2 - (hydrox...
MMEECCHHAANNIISSMM OOFF AACCTTIIOONN 
Inhibitor of viral DNA synthesis 
Initially phosphorylated by viral thymidine kina...
TTRRIIFFLLUURRIIDDIINNEE 
Fluorinated pyrimidine nucleoside that 
has an in vitro inhibitory activity against 
HSV 1 & 2 ...
Title: Trifluridine 
CAS Registry Number: 70-00-8 
CAS Name: a,a,a-Trifluorothymidine 
Additional Names: 2¢-deoxy-5-(trifl...
MMEECCHHAANNIISSMM OOFF AACCTTIIOONN 
Trifluridine monophosphate 
irreversibly inhibits thymidylate 
synthetase 
Triflur...
VVIIDDAARRAABBIINNEE 
Adenosine analog with an in vitro activity 
against HSV, VZV, and CMV 
Phosphorylated intracellula...
Title: Vidarabine 
CAS Registry Number: 5536-17-4 
CAS Name: 9-b-D-Arabinofuranosyl-9H-purine-6-amine monohydrate 
Additio...
TThheerraappeeuuttiicc UUssaaggee 
3% ointment – acute 
keratoconjunctivitis, superficial 
keratitis, recurrent epithelia...
DDOOCCOOSSAANNOOLL 
Saturated 22-carbon aliphatic alcohol. 
Inhibits FUSION between plasma 
membrane and HSV envelope re...
AANNTTII--CCMMVV AAGGEENNTTSS
GGAANNCCIICCLLOOVVIIRR 
(9-[1,3-dihydroxy-2-prepoxymethyl]guanine) 
Cyclic guanosine analog that requires 
triphosphoryla...
Title: Ganciclovir 
CAS Registry Number: 82410-32-0 
CAS Name: 2-Amino-1,9-dihydro-9-[[2-hydroxy-1-(hydroxymethyl)ethoxy]m...
GGaanncciilloovviirr ssyynntthheessiiss
ddeessccrriippttiioonn 
The reaction of epichlorohydrin (I) with benzyl alcohol (II) by means of 
NaOH in water gives 1,3-...
MMEECCHHAANNIISSMM OOFF AACCTTIIOONN 
Monophosphorylated intracellularly by a virus-induced 
enzyme 
Phosphorylation is ...
VVAALLGGAANNCCIICCLLOOVVIIRR 
 L- valyl ester prodrug of ganciclovir 
 Hydrolyzed to active compound ganciclovir by inte...
vvaallggaanncciicclloovviirr
CCIIDDOOFFOOVVIIRR 
(1-[(S)-3-hydroxy-2-(phosphonomethoxy)- 
propyl]cytosine dihydrate) 
 Cytidine nucleoside analog with...
Brodfuehrer, P (1994). "A practical synthesis of (S)- 
HPMPC". Tetrahedron Letters 35: 3243. doi: 
10.1016/S0040-4039(00)7...
FFOOSSCCAARRNNEETT 
Phosphonoformic Acid Inorganic 
Pyrophosphate analog that inhibits viral 
DNA polymerase, RNA polymera...
SSIIDDEE EEFFFFEECCTTSS 
Nephrotoxicity 
Symptomatic hypocalcemia 
Saline loading may reduce the 
risk of nephrotoxicit...
FFOOMMIIVVIIRRSSEENN 
21 mer-phosphorothioate oligonucleotide 
First FDA approved anti-sense therapy. 
Binding to target ...
AANNTTIIRREETTRROOVVIIRRAALL 
AAGGEENNTTSS
NNUUCCLLEEOOSSIIDDEE RREEVVEERRSSEE 
TTRRAANNSSCCRRIIPPTTAASSEE 
IINNHHIIBBIITTOORRSS((NNRRTTIIss)) 
Competitive inhibiti...
ZZIIDDOOVVUUDDIINNEE 
((AAzziitthhyymmiiddiinnee,, AAZZTT)) 
Deoxythymidine analog 
Decrease rate of clinical disease pr...
DDIIDDAANNOOSSIINNEE ((ddddll)) 
Synthetic analog of deoxyadenosine 
Activity is potentiated by hydroxyurea due to 
depl...
EEMMTTRRIICCIITTAABBIINNEE 
 Formerly called FTC 
 Fluorinated analogue of LAMIVUDINE with a long 
intracellular half-li...
LLAAMMIIVVUUDDIINNEE ((33TTCC)) 
Cytosine analog ,synergistic with other 
antiretroviral nucleoside – Stavudine, 
Zidovud...
ZZAALLCCIITTAABBIINNEE ((ddddCC)) 
Cytosine analog with synergistic anti-HIV1 
activity with a variety of antiretrovirals...
SSTTAAVVUUDDIINNEE ((dd44TT)) 
Thymidine analog 
High oral bioavailability, not food dependent 
Renal excretion thru GF...
AABBAACCAAVVIIRR 
Guanosine analog 
Well absorbed during oral administration 
Metabolized by alcohol dehydrogenase 
and...
NNUUCCLLEEOOTTIIDDEE IINNHHIIBBIITTOORR
TTEENNOOFFOOVVIIRR 
Acyclic nucleoside phosphonate 
competitively inhibits HIV reverse 
transcriptase and cause chain 
te...
NNEEVVIIRRAAPPIINNEE 
Oral bioavailability is > 90% 
Not food dependent 
Used as a component of a combination 
antiretr...
DDEELLAAVVIIRRDDIINNEE 
Oral bioavailability of about 85 % 
Metabolized to inactive metabolites by the 
CYP3A & CYP2D6 P...
EEFFAAVVIIRREENNZZ 
Principally metabolized by CYP3A4 & CYP2B6 
to inactive hydroxylated metabolites 
Principal adverse ...
PPRROOTTEEAASSEE IINNHHIIBBIITTOORRSS 
Protease--responsible for cleaving 
precursor molecules (immature budding 
particl...
SSAAQQUUIINNAAVVIIRR 
Saquinavir H- hard gel capsule – poor 
bioavailability, should be taken within 2 hrs 
after a fatty...
RRIITTOONNAAVVIIRR 
An inhibitor of HIV 1 & HIV 2 proteases 
High bioavailability that is increased 
with food 
Common ...
IINNDDIINNAAVVIIRR 
Specific inhibitor of HIV- 1 & HIV-2 proteases 
Higher CSF penetration 
Must be consumed in empty s...
NNEELLFFIINNAAVVIIRR 
Higher absorption in the fed state 
Common adverse effects: diarrhea & 
flatulence
AAMMPPRREENNAAVVIIRR 
Rapidly absorbed from the GIT and 
can be taken with or without food 
High fat meals decrease abso...
FFUUSSIIOONN IINNHHIIBBIITTOORR
EENNFFUUVVIIRRTTIIDDEE ((TT--2200)) 
Newly approved antiretroviral agent 
Blocks entry into the cell 
A synthetic 36-am...
ANTI-HHEEPPAATTIITTIISS AAGGEENNTTSS
AADDEEFFOOVVIIRR 
Phosphorylated by cellular kinases 
to the active diphosphate metabolite 
Competitively inhibits HBV D...
EENNTTEECCAAVVIIRR 
Oral guanosine nucleoside analog 
Competitively inhibits all 3 functions of HBV 
DNA polymerase—base...
IINNTTEERRFFEERROONN AALLFFAA 
Endogenous proteins that exert complex 
antiviral immunomodulatory & antiproliferative 
ac...
IINNTTEERRFFEERROONN AALLPPHHAA 22aa 
Approved for the treatment of chronic 
Hepatitis C, AIDS associated Kaposi’s 
sarco...
AADDEEFFOOVVIIRR 
Phosphorylated by cellular kinases 
to the active diphosphate metabolite 
Competitively inhibits HBV D...
EENNTTEECCAAVVIIRR 
Oral guanosine nucleoside analog 
Competitively inhibits all 3 functions of HBV 
DNA polymerase—base...
IINNTTEERRFFEERROONN AALLFFAA 
Endogenous proteins that exert complex 
antiviral immunomodulatory & antiproliferative 
ac...
IINNTTEERRFFEERROONN AALLPPHHAA 22aa 
Approved for the treatment of chronic 
Hepatitis C, AIDS associated Kaposi’s 
sarco...
IINNTTEERRFFEERROONN AALLPPHHAA 22bb 
Only preparation licensed for treatment of 
HBV & acute HCV 
Leads to loss of HbeA...
PPEEGGYYLLAATTEEDD IINNTTEERRFFEERROONN AALLFFAA 
Recently introduced for treatment of 
chronic hepatitis C 
Longer dura...
RRIIBBAAVVIIRRIINN 
Guanosine analog that is phosphorylated 
intracellularly by host cell enzymes 
Interferes w/ the syn...
ANTI-IINNFFLLUUEENNZZAA AAGGEENNTTSS
AMANTADINE/RRIIMMAANNTTAADDIINNEE 
(1-aminoadamantane hydrochloride) 
a-methyl derivative - rimantadine 
Inhibits uncoa...
OSELTAMIVIR/ZZaannaammiivviirr 
Neuroaminidase inhibitors 
Inhibits replication of 
both influenza A & B 
5 day course r...
UUNNCCLLAASSSSIIFFIIEEDD
PPAALLIIVVIIZZUUMMAABB 
Prevention of RSV in high risk 
infants—premature and those with 
broncho dysplasia and congenita...
To take full advantage of Chemical Web content, it is essential 
to use several Software:Winzip,Chemscape Chime, Shockwave...
TTHHAANNKK YYOOUU!! 
DR ANTHONY CRASTO 
amcrasto@gmail.com 
http://newdrugapprovals.org/
Anti viral-drug synthesis by Dr Anthony Crasto
Anti viral-drug synthesis by Dr Anthony Crasto
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Anti viral-drug synthesis by Dr Anthony Crasto

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Anti viral-drug synthesis by Dr Anthony Crasto

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Anti viral-drug synthesis by Dr Anthony Crasto

  1. 1. SYNTHESIS OOFF AANNTTII--VVIIRRAALL AAGGEENNTTSS DR ANTHONY MELVIN CRASTO Ph.D 2014 PRINCIPAL SCIENTIST PROCESS RESEARCH
  2. 2. This iiss aa vvaasstt ttooppiicc aanndd aa sshhoorrtt oovveerrvviieeww iiss ggiivveenn aanndd iinn nnoo wwaayy ccoommpplleettee jjuussttiiccee ccaann bbee ddoonnee ffoorr tthhiiss
  3. 3. DDeeddiiccaatteedd ttoo mmyy ssoonn LLiioonneell CCrraassttoo,, He was only in first standard in school (dec2007) when I was Paralysed head to toe. His smiling face sees me through day in and day out. Vast readership from academia and industry motivates me, and keeps me going. I am helping millions with free advertisement free websites and has million hits on google Thanks for helping me to keep lionel smiling
  4. 4. AANNTTII--VVIIRRAALL AAGGEENNTTSS VIRUSES: Single or double stranded DNA or RNA enclosed in a protein – CAPSID Obligate intracellular parasite Replication depends on synthetic processes of the host cell Anti-viral drugs must either block entry or exit from cell or be active inside the host cell
  5. 5. VVIIRRAALL RREEPPLLIICCAATTIIOONN  Viral attachment and entry (enfuvirtide, docosanol, palivizumab)  Adsorption and penetration into susceptible host cells (Globulins and interferon-alfa)  Un-coating of viral nucleic acid (Amantadine)  Synthesis of early regulatory proteins (Fomivirsen)  Synthesis of RNA or DNA (RT Inhibitors)  Synthesis of late regulatory proteins (Protease Inhibitors)  Packing and Assembly (maturation) of viral particles (Rifampicin)  Release from cells (Neuraminidase Inhibitors)
  6. 6. AANNTTII--VVIIRRAALL AAGGEENNTTSS Anti-Herpes Acyclovir Famciclovir Valacyclovir Ganciclovir Valganciclovir Lamivudine Vidarabine Idoxuridine Trifluridine Cidofovir Sorivudine Fomivirsen Penciclovir
  7. 7. Anti-retroviral Agents Nucleoside RT inhibitors. Zidovudine Zalcitabine Didanosine Stavudine Lamivudine Abacavir Emtricitabine Non-nucleoside RT Inhibitors Nevirapine Delavirdine Efavirenz
  8. 8. AANNTTII--HHeeppaattiittiiss BB Lamivudine Adenofovir Dipivoxil Entecavir Interferon alfa-2b Famciclovir ANTI-Hepatitis C Pegylated interferon alfa-2a and 2b Ribavirin, interferon alfa 2a, 2b, alfacon
  9. 9. PPrrootteeaassee IInnhhiibbiittoorrss Saquinavir Lopinavir/Ritonavir Indinavir Nelfinavir Amprenavir Darunavir Atazanavir Tipranavir Fosamprenavir
  10. 10. AAnnttii--iinnfflluueennzzaa AAggeennttss Amantadine Rimantadine Neuraminidase Inhibitors Oseltamivir (Tamiflu) Zanamivir Ribavirin Palivizumab Interferons
  11. 11. MMiisscceellllaanneeoouuss Immuno-modulating Agents Inosiplex Isoprinosine Foscarnet
  12. 12. AANNTTII--HHEERRPPEESS AANNTTII--VVAARRIICCEELLLLAA ZZOOSSTTEERR
  13. 13. AACCYYCCLLOOVVIIRR 2-Amino-1,9-dihydro-9-((2-hydroxyethoxy)methyl)-6H-Purin- 6-one Acyclovir(9-[2-hydroxy methyl]-9-H-guanine)  Acyclic guanosine derivative against HSV1, HSV2, and VZV  Weaker activity against EBV, CMV and Human Herpes Virus 6 (HHV 6)
  14. 14. Title: Acyclovir CAS Registry Number: 59277-89-3 CAS Name: 2-Amino-1,9-dihydro-9-[(2-hydroxyethoxy)methyl]-6H-purin-6-one Additional Names: acycloguanosine; 9-[(2-hydroxyethoxy)methyl]guanine Manufacturers' Codes: BW-248U; Wellcome 248U Trademarks: Acicloftal (Bruschettini); Avirase (Lampugnani); Cycloviran (Sigma-Tau); Maynar (Ferrer); Virmen (Menarini); Viruseen (Hommel); Zoliparin (Mann); Zovir (GSK); Zovirax (GSK) Molecular Formula: C8H11N5O3 Molecular Weight: 225.20 Percent Composition: C 42.67%, H 4.92%, N 31.10%, O 21.31% Literature References: Orally active acyclic nucleoside with inhibitory activity towards several herpes viruses. Prepn: H. J. Schaeffer, DE 2539963; idem, US 4199574 (1976, 1980 to Wellcome). Convenient synthesis from guanine: H. Matsumoto et al.,Chem. Pharm. Bull. 36, 1153 (1988). Selectivity of action: G. B. Elion et al., Proc. Natl. Acad. Sci. USA 74, 5716 (1977). Chemistry, antiviral activity, metabolism: H. J. Schaeffer et al., Nature 272, 583 (1978). In vitro activity: P. Collins, D. J. Bauer, J. Antimicrob. Chemother. 5, 431 (1979). Effect on herpes simplex infections in mice: H. J. Field et al., Antimicrob. Agents Chemother. 15, 554 (1979); on herpes zoster in immunocompromised patients: H. H. Balfour et al., N. Engl. J. Med. 308, 1448 (1983). Treatment of primary episodes of genital herpes simplex infection: Y. J. Bryson et al., ibid. 916; of recurrent genital herpes: S. E. Straus et al., ibid. 310, 1545 (1984); J. M. Douglas et al., ibid. 1551. HPLC determn in serum and clinical pharmacokinetics: G. Bahrami et al., J. Chromatogr. B 816, 327 (2005). Symposia on pharmacology and clinical studies: Am. J. Med. 73, Suppl. 1A, 1-392 (1982); J. Antimicrob. Chemother. 12, Suppl. B, 1-202 (1983); Scand. J. Infect. Dis. Suppl. 47, 1-176 (1985). Review: R. J. Whitley, J. W. Gnann, Jr., N. Engl. J. Med. 327, 782-789 (1992). Properties: Crystals from methanol, mp 256.5-257°. LD50 in mice (mg/kg): >10,000 orally; 1000 i.p. (Schaeffer). Melting point: mp 256.5-257° Toxicity data: LD50 in mice (mg/kg): >10,000 orally; 1000 i.p. (Schaeffer) Therap-Cat: Antiviral. Keywords: Antiviral; Purines/Pyrimidinones.
  15. 15. Structures of guanosine and acyclovir compared
  16. 16. SSYYNNTTHHEESSISS
  17. 17. DDeessccrriippttiioonn The reaction of benzonitrile (I) with refluxing ethylene glycol (II) gives ethylene glycol monobenzoate (III), which is chloromethylated with formaldehyde a and dry HCl in CH2Cl2 affording 1-benzoyloxy-2-chloromethoxyethane (IV). The condensation of (IV) with 2,6-dichloropurine (V) by means of triethylamine in DMF yields 2,6-dichloro-9-(2- benzoyloxyethoxymethyl)purine (VI), which is aminated and debenzoylated by treatment with NH3 in methanol at 95 C in a pressure vessel giving 2-chloro-9-(2- hydroxyethoxymethyl)adenine (VII). The Sandmeyer reaction of (VII) with N aNO2 in acetic acid affords 2-chloro-9-(2-hydroxyethoxymethyl)hypoxanthine (VIII), which is finally amonolyzed with ammonia in methanol at 125 C in a pressure vessel.
  18. 18. TTHHEERRAAPPEEUUTTIICC UUSSEESS ACUTE HERPES ZOSTER (SHINGLES) SYSTEMIC ACYCLOVIR PROPHYLAXIS HSV ENCEPHALITIS ( IV form) VARICELLA ZOSTER VIRUS INFECTION CMV PROPHYLAXIS
  19. 19. VVAALLAACCYYCCLLOOVVIIRR (S)-2-[(2-amino-6-oxo-6,9-dihydro-3H-purin-9-yl)methoxy]ethyl-2-amino-3- methylbutanoate  L- valyl ester of acyclovir  Rapidly converted to acyclovir after oral administration  Serum levels are 3-5x greater than acylcovir  Treatment of primary and recurrent genital herpes and herpes zoster infections  Prevents CMV disease in post-transplant patients
  20. 20. Title: 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)
  21. 21. SSYYNNTTHHEESSISS
  22. 22. DDEESSCCRRIPPTTIOONN 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.
  23. 23. FFAAMMCCIICCLLOOVVIIRR 2-[(acetyloxy)methyl]-4-(2-amino-9H-purin-9-yl)butyl acetate  Diacetyl ester prodrug of 6 deoxy penciclovir and rapidly converted to PENCICLOVIR by FIRST-PASS metabolism  Penciclovir does not cause chain termination  Oral form is approved for managing HSV and VZV infections
  24. 24. Title: Famciclovir CAS Registry Number: 104227-87-4 CAS Name: 2-[2-(2-Amino-9H-purin-9-yl)ethyl]-1,3-propanediol diacetate (ester) Additional Names: 9-[4-acetoxy-3-(acetoxymethyl)but-1-yl]-2-aminopurine; FCV Manufacturers' Codes: BRL-42810 Trademarks: Oravir (SKB); Famvir (SKB) Molecular Formula: C14H19N5O4 Molecular Weight: 321.33 Percent Composition: C 52.33%, H 5.96%, N 21.79%, O 19.92% Literature References: Prodrug of penciclovir, q.v. Prepn: M. R. Harnden, R. L. Jarvest, AU 85 47560; eidem, US 5246937 (1986, 1993 both to Beecham); M. R. Harnden et al., J. Med. Chem. 32, 1738 (1989). HPLC determn in plasma and urine: J. R. McMeekin et al., Anal. Proc. 29, 178 (1992). Review of metabolism and mode of action: R. A. Vere Hodge, Antiviral Chem. Chemother. 4, 67-84 (1993). Series of articles on pharmacology and pharmacokinetics: ibid. Suppl. 1, 37-68 (1993). Review of clinical efficacy in herpes zoster and genital herpes: R. Circelli et al., Antiviral Res. 29, 141-151 (1996). Properties: White shiny plates from ethyl acetate-hexane, mp 102-104°. uv max (methanol): 222, 244, 309 nm (e 27500, 4890, 7160). Sol in water (25°): >25% w/v initially; rapidly ppts as sparingly sol monohydrate (2-3% w/v). Freely sol in acetone, methanol; sparingly sol in ethanol, isopropanol. Melting point: mp 102-104° Absorption maximum: uv max (methanol): 222, 244, 309 nm (e 27500, 4890, 7160) Therap-Cat: Antiviral. Keywords: Antiviral; Purines/Pyrimidinones.
  25. 25. FFAAMMCCIICCLLOOVVIIRR First episode genital herpes 250 mg TID for 5-10 days Recurrent genital herpes – 250 mg BID for 1 year Herpes zoster of 3 days – 500 mg TID x 10 days It is as effective as acyclovir in reducing healing time and zoster associated pain Famciclovir is a guanine analogue antiviral drug used for the treatment of various herpesvirus infections, most commonly for herpes zoster (shingles). It is aprodrug form of penciclovir with improved oral bioavailability. Famciclovir is marketed under the trade name Famvir (Novartis). On August 24, 2007, the United States Food and Drug Administration approved the first generic version of famciclovir. Generic Famciclovir Tablets (125 mg, 250 mg, 500 mg) are manufactured by TEVA Pharmaceuticals and Mylan Pharmaceuticals.
  26. 26. DDEESSCCRRIIPPTTIIOONN Synthesis This compound has been obtained by two similar ways (Scheme 10704402a): 1) The reaction of 6-chloropurine-2-amine (I) with 6,6-dimethyl-5 ,7-dioxaspiro [2,5] octane-4 ,8-dione (II) by means of K2CO3 in DMF gives the expected condensation product (III), which is methanolized with HCl / methanol yielding 2 - [2 - (2-amino-6-methoxypurin-9-yl ) ethyl] malonic acid dimethyl ester (IV). The reduction of (IV) with NaBH4 in t-butanol/methanol affords the corresponding diol (V), which is finally converted into pecnciclovir by hydrolysis with 2N NaOH. 2) The reaction of purine (I) with 3-bromopropane-1 ,1,1-tricarboxylic acid triethyl ester (VI) by means ofK2CO3 in DMF gives the expected condensation product (VII), which is partially decarboxylated with sodium methoxide in methanol yielding 2 - [2 - (2-amino-6-chloropurin-9-yl) ethyl] malonic acid diethyl ester (VIII). The reduction of (VIII) with NaBH4 in t-butanol/methanol followed by acetylation with acetic anhydride affords the corresponding diol diacetate ( IX), which is finally converted into penciclovir by hydrlysis with 2N HCl. Synthesis of 126242: A synthesis of famciclovir that corresponds to that previously published and studies on its oral bioavailability in rats and mice, identifying famciclovir as the preferred prodrug of BRL-39123 (penciclovir), have been published. (Scheme 12624201a)
  27. 27. FFAAMMCCIICCLLOOVVIIRR Comparable to valacyclovir in treating zoster and reducing associated pain in older adults 500 mg TID x 10 days is comparable to high dose of acyclovir in treating zoster in immuno-compromised patients and in opthalmic zoster Associated with dose-related reductions in Hepatitis B Virus DNA and transaminase levels in patients with chronic HBV hepatitis
  28. 28. PPEENNCCIICCLLOOVVIIRR 2-amino-9-[4-hydroxy-3-(hydroxymethyl)butyl]-6,9-dihydro-3H-purin- 6-one Penciclovir (9-[4-hydroxy-3-hydroxymethyl but-1-yl] guanine  An acyclic guanine nucleoside  Active metabolite of famciclovir  Spectrum of activity and potency against HSV & VZV is similar to acyclovir  Inhibitory activity to HSV
  29. 29. Title: Penciclovir CAS Registry Number: 39809-25-1 CAS Name: 2-Amino-1,9-dihydro-9-[4-hydroxy-3-(hydroxymethyl)butyl]-6H-purin-6-one Additional Names: 9-[4-hydroxy-3-(hydroxymethyl)but-1-yl]guanine; PCV Manufacturers' Codes: BRL-39123 Trademarks: Denavir (SKB); Vectavir (SKB) Molecular Formula: C10H15N5O3 Molecular Weight: 253.26 Percent Composition: C 47.42%, H 5.97%, N 27.65%, O 18.95% Literature References: Carba analog of ganciclovir, q.v., active against several herpes viruses. Prepn: U. K. Pandit et al., Synth. Commun. 2, 345 (1972); R. L. Jarvest, M. R. Harnden, US 5075445 (1991 to Beecham). Synthesis: M. R. Harnden et al., J. Med. Chem. 30, 1636 (1987); J. Hannah et al., J. Heterocycl. Chem. 26, 1261 (1989). Crystal and molecular structures: M. R. Harndenet al., Nucleosides Nucleotides 9, 499 (1990). In vitro activity of enantiomers in comparison with acyclovir, q.v.: G. Abele et al.,Antiviral Chem. Chemother. 2, 163 (1991); against herpes simplex viruses: A. Weinberg et al., Antimicrob. Agents Chemother. 36,2037 (1992). Clinical pharmacokinetics: S. E. Fowles et al., Eur. J. Clin. Pharmacol. 43, 513 (1992). HPLC determn in plasma and urine: J. R. McMeekin et al., Anal. Proc. 29, 178 (1992). Review of development and antiviral activity: M. R. Harnden, Drugs Future14, 347-358 (1989). Properties: White crystalline solid from water, (monohydrate), mp 275-277°; also reported as colorless matted needles, mp 272-275°. uv max (in water): 253 nm (e 11500). uv max (aq 0.01N NaOH): 215, 268 nm (e 18140, 10710). Sol in water (20°): 1.7 mg/ml, pH 7. Melting point: mp 275-277°; mp 272-275° Absorption maximum: uv max (in water): 253 nm (e 11500); uv max (aq 0.01N NaOH): 215, 268 nm (e 18140, 10710) Derivative Type: Sodium salt Manufacturers' Codes: BRL-39123A Properties: Occurs as monohydrate, stable crystalline solid. Sol in water (20°): >200 mg/ml. 30 mg/ml soln has pH 11. Therap-Cat: Antiviral. Keywords: Antiviral; Purines/Pyrimidinones.
  30. 30. PPEENNIICCIICCLLOOVVIIRR Penciclovir (INN) is a guanine analogue antiviral drug used for the treatment of various herpesvirus infections. It is a nucleoside analogue which exhibits low toxicity and good selectivity. Because penciclovir is absorbed poorly when given orally (by mouth) it is used more as a topical treatment, and is the active ingredient in the cold sore medications Denavir (NDC 0135-0315-52), Vectavir and Fenistil. Famciclovir is a prodrug of penciclovir with improved oral bioavailability.
  31. 31. SSYYNNTTHHEESSIISS
  32. 32. DDEESSCCRRIIPPTTIIOONN The synthesis of penciclovir by two related ways has been reported: 1) The reaction of 2 - (hydroxymethyl) butane-1 ,4-diol (I) with formaldehyde (or an aldehyde such as trimethylacetaldehyde) (II) by means of H2SO4 ( or p-toluenesulfonic acid, TsOH) gives the dioxane (III), which by reaction first with methanesulfonyl chloride and triethylamine and then with NaI in acetone affords the corresponding 5 - (2-iodoethyl) -1,3-dioxane (IV). The reaction of (IV) with 2-amino-6-chloropurine (V) by means of K2CO3 in DMF gives the corresponding condensation product (VI), which is finally hydrolyzed and deprotected with refluxing 2M aqueous HCl. 2) The reaction of triol (I) with 2,2-dimethoxypropane (VII) by means of TsOH gives the corresponding 1,3-dioxane (VIII), which by reaction with triphenylphosphine and CBr4 is converted to the 5 - (2-bromoethyl) derivative (IX) . The reaction of (IX) with the purine (V) by means of K2CO3 as before affords the corresponding condensation product (X), which is hydrolyzed and deprotected with 2M HCl as before.
  33. 33. MMEECCHHAANNIISSMM OOFF AACCTTIIOONN Inhibitor of viral DNA synthesis Initially phosphorylated by viral thymidine kinase Penciclovir triphosphate has a lower affinity in competitive inhibition of viral DNA polymerase thus can not cause chain termination 100 fold less potent in inhibiting DNA polymerase than acyclovir but present in higher concentration and prolonged period in infected cells
  34. 34. TTRRIIFFLLUURRIIDDIINNEE Fluorinated pyrimidine nucleoside that has an in vitro inhibitory activity against HSV 1 & 2 , CMV, vaccinia and certain adenoviruses Inhibits viral DNA synthesis Phosphorylated intracellularly into its active form by cellular enzymes Incorporation into both viral and cellular DNA prevents its systemic use
  35. 35. Title: Trifluridine CAS Registry Number: 70-00-8 CAS Name: a,a,a-Trifluorothymidine Additional Names: 2¢-deoxy-5-(trifluoromethyl)uridine; 5-(trifluoromethyl)-2¢-deoxyuridine; F3TDR Manufacturers' Codes: NSC-75520 Trademarks: TFT Thilo (Alcon-Thilo); Virophta (Dulcis); Viroptic (Burroughs Wellcome) Molecular Formula: C10H11F3N2O5 Molecular Weight: 296.20 Percent Composition: C 40.55%, H 3.74%, F 19.24%, N 9.46%, O 27.01% Literature References: Prepn: C. Heidelberger et al., J. Am. Chem. Soc. 84, 3597 (1962); eidem, J. Med. Chem. 7, 1 (1964); C. Heidelberger, US 3201387 (1965 to U.S. Dept. HEW). Crystal structure: A. H. Tench, Diss. Abstr. Int. B 33, 3587 (1973). NMR study: R. J. Cushley et al., J. Am. Chem. Soc. 90, 709 (1968). Metabolism: D. L. Dexter et al., Cancer Res. 32, 247 (1972); W. J. O'Brien, H. F. Edelhauser, Invest. Ophthalmol. Visual Sci. 16, 1093 (1977). Pharmacodynamics: B. L. Wigdahl, J. R. Parkhurst,Antimicrob. Agents Chemother. 14, 470 (1978); G. J. Smith et al., Biochem. Biophys. Res. Commun. 83, 1538 (1978). Teratogenicity study: M. Itoi et al., Arch. Ophthalmol. 93, 46 (1975). Cytotoxicity and mutagenicity study: E. Huberman, C. Heidelberger, Mutat. Res. 14, 130 (1972). Clinical studies: H. E. Kaufman, Invest. Ophthalmol. Visual Sci. 17, 941 (1978); R. A. Hyndiuk et al., Arch. Ophthalmol. 96, 1839 (1978). Review of mechanism of antiviral activity: C. Heidelberger, Ann. N.Y. Acad. Sci.255, 317 (1975). Review of pharmacology and therapeutic use: A. A. Carmine et al., Drugs 23, 329-353 (1982). Properties: Cryst from ethyl acetate, mp 186-189°. uv max (0.1N HCl): 260 nm (e 9960); (0.1N NaOH): 260 nm (e 6590). Melting point: mp 186-189° Absorption maximum: uv max (0.1N HCl): 260 nm (e 9960); (0.1N NaOH): 260 nm (e 6590) Therap-Cat: Antiviral (ophthalmic).
  36. 36. MMEECCHHAANNIISSMM OOFF AACCTTIIOONN Trifluridine monophosphate irreversibly inhibits thymidylate synthetase Trifluridine triphosphate is a competitive inhibitor of thymidine triphosphate incorporation into DNA by DNA polymerases
  37. 37. VVIIDDAARRAABBIINNEE Adenosine analog with an in vitro activity against HSV, VZV, and CMV Phosphorylated intracellularly by host enzymes to form ara-ATP and then inhibits viral DNA polymerase Vidarabine triphosphate is incorporated into both viral and cellular DNA Rapidly metabolized in vivo to hypoxanthine arabinoside through removal of 6-amino group by adenosine deaminase – decrease viral activity
  38. 38. Title: Vidarabine CAS Registry Number: 5536-17-4 CAS Name: 9-b-D-Arabinofuranosyl-9H-purine-6-amine monohydrate Additional Names: 9-b-D-arabinofuranosyladenine monohydrate; arabinosyladenine; adenine arabinoside; spongoadenosine; ara-A Manufacturers' Codes: CI-673 Trademarks: Arasena-A (Mochida); Vira-A (Warner-Lambert) Molecular Formula: C10H13N5O4.H2O Molecular Weight: 285.26 Percent Composition: C 42.10%, H 5.30%, N 24.55%, O 28.04% Literature References: Purine nucleoside first synthesized as a potential anticancer agent: Lee et al., J. Am. Chem. Soc. 82,2648 (1960); Reist et al., J. Org. Chem. 27, 3274 (1962); Glaudemans, Fletcher, ibid. 28, 3004 (1963); Reist et al., ibid. 29, 3725 (1964). Fermentation process using a strain of Streptomyces antibioticus: GB 1159290; J. D. Howells, A. Ryder, US 3616208(1969, 1971 both to Parke, Davis). Crystal and molecular structure: Bunick, Voet, Acta Crystallogr. 30B, 1641 (1974). Series of articles on antiviral activity: Antimicrob. Agents Chemother. 1968, 136-179. Toxicity study: S. M. Kurtz et al., ibid. 180. HPLC determn in plasma and urine: W. P. McCann et al., ibid. 28, 265 (1985). Clinical trial in immunocompromised patients: R. J. Whitley et al., J. Infect. Dis. 165, 450 (1992). Book: Adenine Arabinoside: An Antiviral Agent, D. Paven-Langston et al., Eds. (Raven Press, New York, 1975) xviii + 425 pp. Review of pharmacology and clinical experience: R. A. Buchanan, F. Hess,Pharmacol. Ther. 8, 143-171 (1980). Comprehensive description: W. Hong et al., Anal. Profiles Drug Subs. 15, 647-672 (1986). Properties: Crystals from water, mp 257.0-257.5° (0.4 H2O). [a]D27 -5° (c = 0.25). uv max (pH 1): 257.5 nm (e 12700); pH 7: 259 nm (e 13400); pH 13: 259 nm (e 14000). LD50 in mice (mg/kg): 4677 i.p.; >7950 orally (Kurtz). Melting point: mp 257.0-257.5° (0.4 H2O) Optical Rotation: [a]D27 -5° (c = 0.25) Absorption maximum: uv max (pH 1): 257.5 nm (e 12700); pH 7: 259 nm (e 13400); pH 13: 259 nm (e 14000) Toxicity data: LD50 in mice (mg/kg): 4677 i.p.; >7950 orally (Kurtz) Therap-Cat: Antiviral. Keywords: Antiviral; Purines/Pyrimidinones.
  39. 39. TThheerraappeeuuttiicc UUssaaggee 3% ointment – acute keratoconjunctivitis, superficial keratitis, recurrent epithelial keratitis (HSV1 and 2) IV vidarabine – HSV encephalitis, neonatal herpes, VZV infection
  40. 40. DDOOCCOOSSAANNOOLL Saturated 22-carbon aliphatic alcohol. Inhibits FUSION between plasma membrane and HSV envelope resulting in prevention of viral entry into cells and subsequent viral replication. Only for orolabial HERPES
  41. 41. AANNTTII--CCMMVV AAGGEENNTTSS
  42. 42. GGAANNCCIICCLLOOVVIIRR (9-[1,3-dihydroxy-2-prepoxymethyl]guanine) Cyclic guanosine analog that requires triphosphorylation for activation prior to inhibiting viral DNA polymerase Similar structure to acyclovir except in having additional hydroxymethyl group on the acyclic side chain
  43. 43. Title: Ganciclovir CAS Registry Number: 82410-32-0 CAS Name: 2-Amino-1,9-dihydro-9-[[2-hydroxy-1-(hydroxymethyl)ethoxy]methyl]-6H-purin-6-one Additional Names: 9-[(1,3-dihydroxy-2-propoxy)methyl]guanine; 2¢-nor-2¢-deoxyguanosine; DHPG; 2¢NDG Manufacturers' Codes: BIOLF-62; BW-B759U; BW-759; BW-759U; RS-21592 Molecular Formula: C9H13N5O4 Molecular Weight: 255.23 Percent Composition: C 42.35%, H 5.13%, N 27.44%, O 25.07% Literature References: Nucleoside analog structurally related to acyclovir, q.v. Prepn: J. P. Verheyden, J. C. Martin, US 4355032(1982 to Syntex); K. K. Ogilvie et al., Can. J. Chem. 60, 3005 (1982); W. T. Ashton et al., Biochem. Biophys. Res. Commun. 108,1716 (1982); J. C. Martin et al., J. Med. Chem. 26, 759 (1983). Antiviral spectrum in vitro: K. O. Smith et al., Antimicrob. Agents Chemother. 22, 55 (1982). Mode of action study: Y.-C. Cheng et al., Proc. Natl. Acad. Sci. USA 80, 2767 (1983). Clinical treatment of cytomegalovirus infection in immunodeficient patients: S. H. Koretz et al., N. Engl. J. Med. 314, 801 (1986). Symposium on pharmacology and clinical efficacy vs cytomegalovirus: Rev. Infect. Dis. 10, Suppl. 3, S457-S572 (1988). Review:C. S. Crumpacker, N. Engl. J. Med. 335, 721-729 (1996). Properties: Crystals from methanol, mp 250° (dec) (Verheyden, Martin); also reported as crystalline monohydrate from water, mp 248-249° (dec) (Ashton); crystals from water, mp >300° (Martin). uv max (methanol): 254 nm (e 12880). Soly in water (25°): 4.3 mg/ml at pH 7. LD50 i.p. in mice: 1-2 g/kg (Martin). Melting point: mp 250° (dec) (Verheyden, Martin); mp 248-249° (dec) (Ashton); mp >300° (Martin) Absorption maximum: uv max (methanol): 254 nm (e 12880) Toxicity data: LD50 i.p. in mice: 1-2 g/kg (Martin) Derivative Type: Sodium salt CAS Registry Number: 107910-75-8 Trademarks: Cymevan (Syntex); Cymevene (Syntex); Cytovene (Syntex); Denosine (Syntex); Vitrasert (Chiron) Molecular Formula: C9H12N5NaO4 Molecular Weight: 277.21 Percent Composition: C 38.99%, H 4.36%, N 25.26%, Na 8.29%, O 23.09% Therap-Cat: Antiviral. Keywords: Antiviral; Purines/Pyrimidinones.
  44. 44. GGaanncciilloovviirr ssyynntthheessiiss
  45. 45. ddeessccrriippttiioonn The reaction of epichlorohydrin (I) with benzyl alcohol (II) by means of NaOH in water gives 1,3-di-O-benzylglycerol (III), which is condensed with paraformaldehyde by means of HCl in methylene chloride to yield 1,3-di-O-benzyl-2-O-(chloromethyl)glycerol (IV). Acetylation of (IV) with potassium acetate in acetone affords 1,3-di-O-benzyl- 2-O-(acetoxymethyl)glycerol (V), which is condensed with diacetylguanine (VI) by means of p-toluenesulfonic acid in sulfolane giving N2-acetyl-9-[[1,3-bis(benzyloxy)-2- propoxy]methyl]guanine (VII). Finally, this compound is deprotected by a treatment with palladium hydroxide in refluxing cyclohexane.
  46. 46. MMEECCHHAANNIISSMM OOFF AACCTTIIOONN Monophosphorylated intracellularly by a virus-induced enzyme Phosphorylation is catalyzed by a viral thymidine kinase during HSV, phosphotransferase UL97 encoded gene during CMV infection Ganciclovir di & triphosphate formed by cellular enzymes Triphosphate is a competitive inhibitor of deoxyguanosine triphosphate incorporation into DNA inhibiting viral rather than cellular DNA polymerase Viral DNA incorporation causes cessation of DNA chain elongation
  47. 47. VVAALLGGAANNCCIICCLLOOVVIIRR  L- valyl ester prodrug of ganciclovir  Hydrolyzed to active compound ganciclovir by intestinal and hepatic enzymes  Well absorbed (60%) & rapidly metabolized in intestinal walls & liver to ganciclovir  Renal excretion thru GN and TS Usage:CMV retinitis in AIDS and for prevention of CMV in high risk kidney, heart transplant.
  48. 48. vvaallggaanncciicclloovviirr
  49. 49. CCIIDDOOFFOOVVIIRR (1-[(S)-3-hydroxy-2-(phosphonomethoxy)- propyl]cytosine dihydrate)  Cytidine nucleoside analog with inhibitory activity against human herpes, papilloma, polyoma, pox, and adenoviruses  Phosphorylation to active disphosphate is independent of viral enzymes  After phosphorylation; it acts as potent inhibitor to viral DNA polymerase
  50. 50. Brodfuehrer, P (1994). "A practical synthesis of (S)- HPMPC". Tetrahedron Letters 35: 3243. doi: 10.1016/S0040-4039(00)76875-4.
  51. 51. FFOOSSCCAARRNNEETT Phosphonoformic Acid Inorganic Pyrophosphate analog that inhibits viral DNA polymerase, RNA polymerase and HIV transcriptase directly without requiring activation by phosphorylation Taken up slowly by cells and does not undergo significant intracellular metabolism Reversibly blocks the pyrophosphate binding site of the viral polymerase Inhibits cleavage of pyrophosphate from deoxynucleotide triphosphates
  52. 52. SSIIDDEE EEFFFFEECCTTSS Nephrotoxicity Symptomatic hypocalcemia Saline loading may reduce the risk of nephrotoxicity Concurrent administration with pentamidine exacerbates both nephrotoxicity and hypocalcemia
  53. 53. FFOOMMIIVVIIRRSSEENN 21 mer-phosphorothioate oligonucleotide First FDA approved anti-sense therapy. Binding to target mRNA results in inhibition of immediate early region 2 protein synthesis – inhibiting viral replication Injected intravitreally in CMV retinitis in AIDS
  54. 54. AANNTTIIRREETTRROOVVIIRRAALL AAGGEENNTTSS
  55. 55. NNUUCCLLEEOOSSIIDDEE RREEVVEERRSSEE TTRRAANNSSCCRRIIPPTTAASSEE IINNHHIIBBIITTOORRSS((NNRRTTIIss)) Competitive inhibition of HIV 1 reverse transcriptase and can be incorporated into the growing viral DNA chain to cause termination Requires intracytoplasmic activation as a result of phosphorylation by cellular enzymes to the triphosphate form Activity against HIV 1, HIV 2 Lactic acidosis & severe hepatomegaly with steatosis
  56. 56. ZZIIDDOOVVUUDDIINNEE ((AAzziitthhyymmiiddiinnee,, AAZZTT)) Deoxythymidine analog Decrease rate of clinical disease progression and prolong survival of HIV infected individuals Well absorbed from the gut and distributed to most body tissues & fluids Eliminated by renal excretion following glucorinadation in the liver Combination therapy with other anti-retroviral agents enhance potency and delay resistance
  57. 57. DDIIDDAANNOOSSIINNEE ((ddddll)) Synthetic analog of deoxyadenosine Activity is potentiated by hydroxyurea due to depletion of intraocular pools of d-ATP Chewable, dispersable tablet, enteric coated Contains phenylalanine and Na Should be taken on an empty stomach Food, fluroquinolones and tetracycline should be given 2 hrs before didanosine
  58. 58. EEMMTTRRIICCIITTAABBIINNEE  Formerly called FTC  Fluorinated analogue of LAMIVUDINE with a long intracellular half-life(>39 hrs)  Oral bioavailability: 93%  CSF level is LOW  Mean plasma half-line: 8-9 hours  Renal excretion thru GF and TS  Contraindicated in children, pregnant women, and patients with renal and hepatic failure (propylene glycol)  Most common side effects-HA, diarrhea, hyper-pigmentation in palms and soles  Can not combine with LAMIVUDINE
  59. 59. LLAAMMIIVVUUDDIINNEE ((33TTCC)) Cytosine analog ,synergistic with other antiretroviral nucleoside – Stavudine, Zidovudine Oral bioavailability exceeds 80% and it is not food dependent Elimination in urine is UNCHANGED Used in combination therapy NOTE: no combination with zalcitabine-may inhibit intracellular phosphorylation of one another thus decreasing potency. Approved for the treatment of chronic Hepatitis B infection
  60. 60. ZZAALLCCIITTAABBIINNEE ((ddddCC)) Cytosine analog with synergistic anti-HIV1 activity with a variety of antiretrovirals against both zidovudine sensitive and resistant strains Associated with dose-dependent peripheral neuropathy Oral and esophageal ulcerations Increase bioavailability in combination with probenecid or cimetidine Decrease bioavailability in combination with antacids and metoclopramide
  61. 61. SSTTAAVVUUDDIINNEE ((dd44TT)) Thymidine analog High oral bioavailability, not food dependent Renal excretion thru GF and TS Major dose-limiting toxicity: Dose-related peripheral sensory neuropathy Pancreatitis, arthralgias, elevation of serum aminotransferases Phosphorylation is reduced by zidovudine
  62. 62. AABBAACCAAVVIIRR Guanosine analog Well absorbed during oral administration Metabolized by alcohol dehydrogenase and glucuronosyl-transferase to inactive metabolites Fatal hypersensitivity reactions Nausea, vomiting, diarrhea, headache, fatigue Hyperglycemia, hypertriglyceridemia and lactic acidosis
  63. 63. NNUUCCLLEEOOTTIIDDEE IINNHHIIBBIITTOORR
  64. 64. TTEENNOOFFOOVVIIRR Acyclic nucleoside phosphonate competitively inhibits HIV reverse transcriptase and cause chain termination after incorporation to DNA Indicated for use in combination with other antiretroviral agents
  65. 65. NNEEVVIIRRAAPPIINNEE Oral bioavailability is > 90% Not food dependent Used as a component of a combination antiretroviral regimen Effective in the prevention of transmission of HIV from mother to newborn Causes severe life threatening rashes
  66. 66. DDEELLAAVVIIRRDDIINNEE Oral bioavailability of about 85 % Metabolized to inactive metabolites by the CYP3A & CYP2D6 P450 enzymes Plasma concentrations are reduced by antacids, didanosine, phenytoin, phenobarbital, carbamazepine, rifabutin, rifampin, nelfinavir & saquinavir Concentrations increased by clarithromycin, fluoxetine, & ketoconazole
  67. 67. EEFFAAVVIIRREENNZZ Principally metabolized by CYP3A4 & CYP2B6 to inactive hydroxylated metabolites Principal adverse effects: CNS (dizziness, drowsiness, insomnia, headache, confusion, amnesia, agitation, delusions, depression, nightmares, euphoria) Pyschiatric symptoms rashes
  68. 68. PPRROOTTEEAASSEE IINNHHIIBBIITTOORRSS Protease--responsible for cleaving precursor molecules (immature budding particles) PI---result in the production of immature, non-infectious viral particles Associated w/ spontaneous bleeding in hemophilia A & B Do not undergo process of phosphorylation
  69. 69. SSAAQQUUIINNAAVVIIRR Saquinavir H- hard gel capsule – poor bioavailability, should be taken within 2 hrs after a fatty meal Saquinavir S – soft gel capsule – improved absorption 3x than hard gel capsule Subject to first pass-metabolism by CYP3A4 Levels are increased by ritonavir, nelfinavir, delavirdine, indinavir, ketoconazole, clarithromycin, & grapefruit juice
  70. 70. RRIITTOONNAAVVIIRR An inhibitor of HIV 1 & HIV 2 proteases High bioavailability that is increased with food Common adverse effects: GIT disturbances, paresthesias, increase aminotransferase level, altered taste, hypertriglyceridemia
  71. 71. IINNDDIINNAAVVIIRR Specific inhibitor of HIV- 1 & HIV-2 proteases Higher CSF penetration Must be consumed in empty stomach for maximal absorption Most common adverse effects are indirect hyperbilirubinemia & nephrolithiasis due to crystalization
  72. 72. NNEELLFFIINNAAVVIIRR Higher absorption in the fed state Common adverse effects: diarrhea & flatulence
  73. 73. AAMMPPRREENNAAVVIIRR Rapidly absorbed from the GIT and can be taken with or without food High fat meals decrease absorption Common adverse effects: nausea, vomiting, diarrhea, peri-oral paresthesias, rash Steven Johnson’s syndrome Inhibits CYP3A4 activity
  74. 74. FFUUSSIIOONN IINNHHIIBBIITTOORR
  75. 75. EENNFFUUVVIIRRTTIIDDEE ((TT--2200)) Newly approved antiretroviral agent Blocks entry into the cell A synthetic 36-amino acid peptide binds to the gp41 subunit of the viral envelope glycoprotein thus preventing the conformational changes required for the fusion of the viral and cellular membranes Administered subcutaneously in combination with other retroviral agents
  76. 76. ANTI-HHEEPPAATTIITTIISS AAGGEENNTTSS
  77. 77. AADDEEFFOOVVIIRR Phosphorylated by cellular kinases to the active diphosphate metabolite Competitively inhibits HBV DNA polymerase Chain termination after incorporation into viral replication
  78. 78. EENNTTEECCAAVVIIRR Oral guanosine nucleoside analog Competitively inhibits all 3 functions of HBV DNA polymerase—base priming, reverse transcription of negative strand and synthesis of positive strand of HBV DNA. Taken by empty stomach half life 15 hours Significantly HIGHER rates of HBV DNA viral suppression than lamivudine.
  79. 79. IINNTTEERRFFEERROONN AALLFFAA Endogenous proteins that exert complex antiviral immunomodulatory & antiproliferative activities through cellular metabolic process Enzyme induction, suppression of cell proliferation, immunomodulatory activities & inhibition of viral replication Inhibition of viral penetration & uncoating Treatment of both HBV & HCV
  80. 80. IINNTTEERRFFEERROONN AALLPPHHAA 22aa Approved for the treatment of chronic Hepatitis C, AIDS associated Kaposi’s sarcoma, hairy cell leukemia, chronic myelogenous leukemia
  81. 81. AADDEEFFOOVVIIRR Phosphorylated by cellular kinases to the active diphosphate metabolite Competitively inhibits HBV DNA polymerase Chain termination after incorporation into viral replication
  82. 82. EENNTTEECCAAVVIIRR Oral guanosine nucleoside analog Competitively inhibits all 3 functions of HBV DNA polymerase—base priming, reverse transcription of negative strand and synthesis of positive strand of HBV DNA. Taken by empty stomach half life 15 hours Significantly HIGHER rates of HBV DNA viral suppression than lamivudine.
  83. 83. IINNTTEERRFFEERROONN AALLFFAA Endogenous proteins that exert complex antiviral immunomodulatory & antiproliferative activities through cellular metabolic process Enzyme induction, suppression of cell proliferation, immunomodulatory activities & inhibition of viral replication Inhibition of viral penetration & uncoating Treatment of both HBV & HCV
  84. 84. IINNTTEERRFFEERROONN AALLPPHHAA 22aa Approved for the treatment of chronic Hepatitis C, AIDS associated Kaposi’s sarcoma, hairy cell leukemia, chronic myelogenous leukemia
  85. 85. IINNTTEERRFFEERROONN AALLPPHHAA 22bb Only preparation licensed for treatment of HBV & acute HCV Leads to loss of HbeAg, normalization of aminotransferases Administered subcutaneously or intramuscularly Hairy cell leukemia, malignant melanoma, follicular non-Hodgkin’s lymphoma, AIDS related kaposi’s sarcoma, & chronic Hepatitis C
  86. 86. PPEEGGYYLLAATTEEDD IINNTTEERRFFEERROONN AALLFFAA Recently introduced for treatment of chronic hepatitis C Longer duration with slower clearance
  87. 87. RRIIBBAAVVIIRRIINN Guanosine analog that is phosphorylated intracellularly by host cell enzymes Interferes w/ the synthesis of guanosine triphosphate Inhibit capping of viral messenger RNA Inhibit viral RNA dependent RNA polymerase of certain viruses Influenza A, parainfluenza, RSV, paramyxoviruses, HCV & HIV 1
  88. 88. ANTI-IINNFFLLUUEENNZZAA AAGGEENNTTSS
  89. 89. AMANTADINE/RRIIMMAANNTTAADDIINNEE (1-aminoadamantane hydrochloride) a-methyl derivative - rimantadine Inhibits uncoating of viral RNA influenza A within infected cell thus preventing replication Effectively reduce the duration of symptoms of influenza when administered within 48 hrs of onset Primary target is M2 proteins
  90. 90. OSELTAMIVIR/ZZaannaammiivviirr Neuroaminidase inhibitors Inhibits replication of both influenza A & B 5 day course regimen for both influenza A & B NOTE: Treatment for Bird Flu
  91. 91. UUNNCCLLAASSSSIIFFIIEEDD
  92. 92. PPAALLIIVVIIZZUUMMAABB Prevention of RSV in high risk infants—premature and those with broncho dysplasia and congenital heart disease. Humanized monoclonal antibody IMQUIMOD •Immune response modifier effective in topical treatment of external genitalia & perianal warts
  93. 93. To take full advantage of Chemical Web content, it is essential to use several Software:Winzip,Chemscape Chime, Shockwave, Adobe Acrobat, Cosmo Player, Web Lab Viewer, Paint Shop Pro, Rasmol, ChemOffice, Quick Time,et
  94. 94. TTHHAANNKK YYOOUU!! DR ANTHONY CRASTO amcrasto@gmail.com http://newdrugapprovals.org/

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