Antiviral Chemistry & Chemotherapy's Current Antiviral Agents Factfile 2006

RNA_title_sheet 22/8/06 10:13 Page 1

Antiviral Chemistry & Chemotherapy’s current antiviral agents FactFile 2006 (1st edition) The RNA viruses RNA_title_sheet 22/8/06 10:13 Page 2 RNA 22/8/06 09:31 Page 129

Antiviral Chemistry & Chemotherapy 17.3 FactFiille:: RNA viiruses

Symmetrel, Mantadix Amantadine Adamantan-1-amine hydrochloride, l-adamantanamine, amantadine hydrochloride. Novartis

References: 1,64,65 Principal target virus: Influenza A virus. Other activities: HCV. H 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.

NH2.HCI 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 H C H 3 O N N OH 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

FactFiille:: RNA viiruses Antiviral Chemistry & Chemotherapy 17.3 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

NH2

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.

NN O

CH3 N CH2 CH2 O C O CH2 CH3

Antiviral Chemistry & Chemotherapy 17.3 FactFiille:: RNA viiruses 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. CH3 O N Capsid-binding agent, structurally related to WIN 54954. Withdrawn due to toxicity concerns (induces cytochrome P-450 3A enzymes). O F CH F 3 F N

CH3 O N

R1479 4′-Azidocytidine. Roche

References: 79,80

Principal target virus: HCV. NH2 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- ated and showed modest viral load reductions at the higher dosing HO regimens. Due to low exposure, R1479 was discontinued in favour N of a R1479 prodrug, R1626. O O

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. H N N Clinical stage: Licensed, patent expired. 2

Known to have additional immunosuppressive effects. N N HO O

HO OH

FactFiille:: RNA viiruses Antiviral Chemistry & Chemotherapy 17.3

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. NH2.HCI

CH3 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-enoic acid 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.

CONH F N 2

Antiviral Chemistry & Chemotherapy 17.3 FactFiille:: RNA viiruses

VX 950 Telaprevir (1S,3aR, 6aS)-2-((S)-2-{(S)-2-Cyclohexyl-2-[(pyrazine-2-carbonyl)-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 N N H O H N O O H N 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.

NH2

N O HO O

CH3

NH2 O OH

FactFiille:: RNA viiruses 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

N H2N 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 CH3 N

O N O O Cl

Antiviral Chemistry & Chemotherapy 17.3 FactFiille:: RNA viiruses

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 NH2 O

FactFiille Antiviral Chemistry & Chemotherapy 17.3 Disclaimer movinyl)-2′-deoxyuridine in severe herpes zoster infections. British Medical Journal 281:1178. 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 Pharmacology 68:2301–2315. 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 Reviews 16:569–596. 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- Acknowledgements methoxyalkyl derivatives of purine and pyrimidines. Antiviral Research 8:261–272. The authors would like to acknowledge the following 13. Lalezari JP, Jaffe HS, Stagg RJ, Ruby AE, Wolitz RA, Simon individuals for contributing information and their time: GL, Weinberg DV, Lewis RA, Johnson M, Youle M, Northfelt DW, Kuppermann BD, Hardy WD, Nelson R, Ives DV, Irina Alymova, Koen Andries, Karen K Biron, David Kemper CA, McKinley GF, Kramer F & Holland GN (1998) Chu, Marc S Collett, Richard J Colonno, Jose Este, Ann Randomized, controlled study of the safety and efficacy of Kwong, Daniel Lamarre, Richard Mackman, Victor E intravenous cidofovir for the treatment of relapsing cytomegalovirus retinitis in patients with AIDS. 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