Antiviral Chemistry & Chemotherapy’s current antiviral agents

16 Pages·2006·0.75 MB·English

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Antiviral Chemistry & Chemotherapy’s current antiviral
agents FactFile 2006 (1st edition)
The RNA viruses
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Symmetrel, Mantadix Amantadine
Adamantan-1-amine hydrochloride,l-adamantanamine,aman-
tadine hydrochloride. Novartis
References:1,64,65
Principal target virus:Influenza A virus.
H
Other activities:HCV.
Mode of action:M2 ion channel inhibitor.
Clinical stage:Licensed.
Adamantine (cyclic primary amine) derivative used for the treatment
and prophylaxis of influenza A virus infections.Rapid emergence of
resistence has limited it use.Sometimes used to treat HCV infection
in combination with interferon and ribavirin.
NH.HCI
2
H
H
Ciluprevir
(1S,4R,6S,14S,18R)-7Z-14-Cyclopentyloxycarbonylamino-18-[2-(2-
isopropylamino-thiazol-4-yl)-7-methoxy-quinolin-4-yloxy]-2,15 Boehringer Ingelheim (Canada) Ltd. R&D
dioxo-3,16-diazatricyclo[14.3.0.04,6]nonadec-7-ene-4-carboxylic acid,
BILN 2061. References:66,67,68,69
OMe
Principal target virus:HCV
Mode of action:PI
Development of ciluprevir has been discontinued.
Ciluprevir is a novel small molecule anti-hepatitis C compound.It is N
the first in a new class of investigational antiviral drugs,HCV PIs.
N H
O N
CH
S 3
O
O N HN OH H3C
O
O N O
H
Tamiflu Oseltamivir
Ethyl ester of (3R,4R,5S)-4-acetamido-5-amino-3-(1-ethyl-
propoxy)-1-cyclohexane-1-carboxylic acid,GS4104,Ro-64-0796. Gilead Sciences/Roche
References:70,71,72
Principal target virus:Influenza A virus.
Other activities:Influenza B virus. O
Mode of action:Influenza virus neuraminidase inhibitor.
Clinical stage:Licensed. O
O
Sialic acid analogue used for the treatment and prophylaxis of
influenza A and B virus infection.Also effective against avian
influenza H5N1 virus.In contrast with zanamivir,oseltamivir can be
given perorally.
HN
NH
O 2
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Peramivir
(1S,2S,3S,4I)-3-[(1S)-1-Acetylamino)]-2-hydroxy-cyclopentane
BioCryst Pharamaceuticals,Inc carboxylic acid,RWJ-270201,BCX-1812.
References:73,74
Principal target virus:Influenza virus.
Mode of action:Influenza virus neuraminidase inhibitor.
Clinical stage:Phase III trials versus influenza virus.
Peramivir showed significant antiviral activity versus influenza A and B in Phase II and III clinical trials,but the primary endpoint of
time to relief of symptoms did not reach statistical significance possibly due to low bioavailability.Threat of H5N1 has renewed interest
in probability of using an oral prodrug.
O
HO
O
H H OH
N
HN
NH
NH
2
Pirodavir
Ethyl-4-[2-[1-(6-methyl-3-pyridazinyl)-4-piperidinyl]ethoxy]benzoate,
Janssen Pharmaceutica R77975.
References:75,76
Principal target virus:Human rhinovirus groups A and B.
Other activities:Some enteroviruses.
Mode of action:Capsid-binding compound.
Clinical stage:Discontinued.
N N O
CH N CH CH O C O CH CH
3 2 2 2 3
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Pleconaril
3-[3,5-Dimethyl-4-[3-(3-methyloxazol-5-yl)propoxy]phenyl]-5-
(trifluoromethyl)-1,2,4-oxadiazole,VP-63843. ViroPharma
References:77,78
Principal target virus:Rhinoviruses.
Mode of action:Capsid-binding protein.
Other activities:Enteroviruses,coxsackievirus.
Clinical stage:Discontinued.
CH O N
3
Capsid-binding agent,structurally related to WIN 54954.Withdrawn
O
due to toxicity concerns (induces cytochrome P-450 3A enzymes).
F CH
F 3
F N
CH
3
O N
R1479
4′-Azidocytidine.
Roche
References:79,80
Principal target virus:HCV. NH
2
Mode of action:R1479 triphosphate inhibits the HCV polymerase
NS5B.
Clinical stage:Completed SAD and MAD Phase I clinical trials.
N
In MAD studies with HCV infected patients,R1479 was well toler-
HO
ated and showed modest viral load reductions at the higher dosing
regimens. Due to low exposure,R1479 was discontinued in favour N
of a R1479 prodrug,R1626. O
O
N
3
HO OH
Virazid/Virazide/Virazole Ribavirin
1-β-D-Ribofuranosyl-1H-1,2,4-triazole-3-carboxamide,ICN-1229,
RTCA,tribavirin. Schering–Plough (formerly ICN Pharmaceuticals)
References:81,82,83
Principal target virus:RSV,HCV. O
Other activities:Influenza virus,lassa,hantaan and others.
Mode of action:Inosine monophosphate dehydrogenase inhibitor,
inhibitor of influenza virus RNA polymerase.
HN N
Clinical stage:Licensed,patent expired. 2
N
Known to have additional immunosuppressive effects.
N
HO
O
HO OH
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Rimantadine Flumadine
1-(1-Adamantyl)ethanamine hydrochloride.
Forest Pharmaceuticals
References:1,65,84
Principal target virus:Influenza A virus.
H Mode of action:M2 ion channel inhibitor.
Clinical stage:Licensed.
Adamantane derivative.Related to amantadine with which it
shows cross-resisitence.Rapid emergence of resistence has limited
it use.
NH.HCI
2
H
CH
3
H
Ruprintrivir
4-{2-(4-Fluoro-benzyl)-6-methyl-5-[(5-methyl-isoxazole-3-
Pfizer Global Research and Development carbonyl)-amino]-4-oxo-heptanoylamino}-5-(2-oxo-pyrro-
lidin-3-yl)-pent-2-enoicacid ethyl ester,AG7088.
References:85,86,87
Principal target virus:Rhinovirus.
O Other activities:Enterovirus.
NH
Mode of action:3C protease inhibtor.
Clinical stage:Phase II.
O
Demonstration of efficacy in Phase II human experimental
human rhinovirus challenge trial,but not in a subsequent Phase II
HN N COOEt natural infection study in patients and thus was terminated for
H clinical development.
O
N O
O
F
T-705
6-Fluoro-3-hydroxy-2-pyrazinecarboxamide.
Toyama Chemical Co.,Ltd
References:88,89,90
Principal target virus:Influenza.
Other activities:Parainfluenza.
Mode of action:Influenza virus RNA polymerase inhibitor.
N Clinical stage:Preclinical.
OH
Investigative new drug application in progress.
F N CONH2
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VX 950 Telaprevir
(1S,3aR,6aS)-2-((S)-2-{(S)-2-Cyclohexyl-2-[(pyrazine-2-car-
bonyl)-amino]-acetylamino}-3,3-dimethyl-butyryl)-octahydro- Vertex Pharmaceuticals
cyclopenta[c]pyrrole-1-carboxylic acid ((S)-1-cyclopropylaminooxa-
lyl-butyl)-amide,VRT-111950,LY570310,MP-424,CAS Registry References:91,92,93
Number 402957-28-2.
Principal target virus:HCV.
Mode of action:HCV NS3•4A inhibitor.
N
O
H
N N
O
N N H
H N
O O H
N
O
O
Valopicitabine
2(S)-Amino-3-methyl-butyric acid,5(R)-[4-amino-2-oxo-2H-
pyrimidine-1-yl]-4(R)-hydroxy-2(R)-hydroxymethyl-4-methyl- Idenix Pharmaceuticals/Novartis Pharmaceuticals
tetrahydro-furan-3(S)-yl ester (dihydrochloride salt),NM 283,3'-
valine ester of 2'-C-methylcytidine,2′-C-methyl-cytidine-3′-O-L- References:94,95
valine ester (dihydrochloride salt).
Principal target virus:HCV.
Mode of action:Nucleoside analogue.
Clinical stage:Phase IIb clinical trials.
Oral prodrug active against HCV-1 infection in the clinic and shows enhanced efficacy in combination with interferon α.Also active
against bovine virus diarrhoea virus in vitro.
NH
2
N
N O
HO
O
CH
3
NH
2
O OH
O
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Viramidine
1-β-D-Ribofuranosyl-1,2,4-triazole-3-carboximidine,ribamidine.
Valeant Pharmaceuticals,Inc
References:96,97,98,99
Principal target virus:HCV.
Other activities:Influenza virus.Members of Bunyaviridae(rift valley fever,sandfly fever,crimean-congo haemorrhagic fever,hantaan virus
infection).
Mode of action:Inosine monophosphate dehydrogenase inhibitor,inhibitor of influenza virus RNA polymerase.
Clinical stage:Phase III versus hepatitis C.
Viramidine is a prodrug of ribavirin
NH
N
HN
2
N
N
HO
O
HO OH
WIN 54954
5-(5-[2,6-Dichloro-4-94,5-dihydro-2-oxazolyl)phenoxy]-
Sterling Winthrop pentyl)-3-methylisoxasole.
References:100,101
Principal target virus:Rhinoviruses.
Other activities:Enteroviruses.
Mode of action:Capsid-binding agent.
Clinical stage:No longer in development.
Cl CH
3
N
O N
O
O
Cl
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Relenza Zanamivir
(4R,5R,6R)-5-acetamido-4-(diaminomethylideneamino)-6-
[(1R,2R)-1,2,3-trihydroxypropyl]-5,6-dihydro-4H-pyran-2-car- GlaxoSmithKline (GSK)
boxylic acid,4-guanidino-Neu5Ac2en,GG167,GR121167X.
References:102,103
Principal target virus:Influenza A viruses.
Other activities:Influenza B viruses. OH O
Mode of action:Influenza virus neuraminidase inhibitor. H
Clinical stage:Licensed.
O
Sialic acid analogue used for the treatment and prophylaxis of OH OH
influenza A and B virus infections.Delivered by inhalation owing to
poor oral bioavailability.
OH
HN
HN NH
2
O
NH
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Disclaimer movinyl)-2′-deoxyuridine in severe herpes zoster infections.
British Medical Journal281:1178.
The authors declare that the current antiviral agent 10. De Clercq E (2004) Discovery and development of BVDU
(brivudin) as a therapeutic for the treatment of herpes zoster.
FactFile is accurate and up-to-date to the best of their
Biochemical Pharmacology68:2301–2315.
knowledge.The authors are happy to receive any comments
11. De Clercq E (2003) Clinical potential of the acyclic nucleoside
or any information about new compounds for inclusion in phosphonates cidofovir,adefovir,and tenofovir in treatment of
future editions,please do not hesitate to contact us by using DNA virus and retrovirus infections.Clinical Microbiology
Reviews16:569–596.
the feedback form provided at the start of the FactFile.
12. De Clercq E,Sakuma T,Baba M,Pauwells R,Balzarini J,
Rosenberg I & Holy A (1987) Antiviral activity of phosphonyl-
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DW,Kuppermann BD,Hardy WD,Nelson R,Ives DV,
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