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Compound Name References: Xxx,Xxx Proprietary Name Systematic/Other Names Notes

Compound Name References: Xxx,Xxx Proprietary Name Systematic/Other Names Notes

Antiviral Chemistry & Chemotherapy 19:75–105 Antiviral Chemistry & Chemotherapy’s current antiviral agents FactFile (2nd edition): retroviruses and hepadnaviruses

Erik De Clercq1 and Hugh J Field1*

1Rega Institute for Medical Research, Leuven, Belgium 2Department of Veterinary Medicine, University of Cambridge, Cambridge, UK

*Corresponding author: E-mail: [email protected]

There are at present exactly 25 compounds that have been used in drug combination regimens. Although, given the formally approved for the treatment of retrovirus (that is number of compounds available, the drug combinations HIV) infections: seven nucleoside reverse transcriptase that could be concocted are uncountable, only one triple- inhibitors (NRTIs), one nucleotide reverse transcriptase drug combination has so far been formulated as single pill inhibitor (NtRTI), four non-nucleoside reverse transcriptase to be taken orally once daily, namely Atripla® containing inhibitors (NNRTIs), 10 protease inhibitors (PIs), one core- the NtRTI fumarate, the NRTI emtric- ceptor inhibitor (CRI), one fusion inhibitor (FI) and one itabine and the NNRTI . Here, we document these (INI). Other compounds expected to be approved compounds along with other HIV-active com- approved for the treatment of HIV infections in the near pounds and, for the first time, compounds whose principal future are the NNRTI , the CRI and the activity is against . The logic of this new INI . To obtain synergistic activity, enable lower division being the enzymatic similarity between the reverse dosage levels, thus minimizing toxic side effects, and par- transcriptase of HIV and hepatitis B virus; the strategies for ticularly to reduce the risk of drug resistance development, the development of antiviral agents to combat them have common wisdom dictates that the HIV inhibitors should be much in common.

Key to FactFile

Company/Institution Compound name References: xxx,xxx Proprietary name Systematic/other names Notes.

Structure

Abbreviation list

BCNA Bicyclic EBV Epstein–Barr virus FIV feline immunodeficiency virus

HBV hepatitis B virus HCMV human cytomegalovirus HHV human herpes virus

HSV herpes simplex virus NNRTI non-nucleoside reverse transcriptase NRTI nucleoside reverse transcriptase inhibitor inhibitor NtRTI nucleotide reverse transcriptase SIV simian immunodeficiency virus VZV varicella-zoster virus inhibitor

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Retroviruses.indd 75 28/7/08 13:47:27 Factfile: Retroviruses GlaxoSmithKline (GSK) References: 1–3 Ziagen® (1S,4R)-4-[2-Amino-6-(cyclopropyl-amino)-9H-purin-9-yl]-2- cyclopentene-1-methanol succinate, 1592U89, ABC, ABV. Principal target virus: HIV-1. Compound class: NRTI. Clinical stage: Licensed. NH Used for the treatment of HIV infections (AIDS). Has been N N coformulated with as Kivexa® and with and lamivudine as Trizivir®. N H2N N HO

ADA Hubriphar SPRL References: 4–6

1,1′-Azobisformamide. Principal target virus: HIV-1. Other activities: HIV-2. Compound class: Nucleocapsid inhibitor. Clinical stage: Under clinical consideration for some time.

Believed to inject zinc from NCp7; effective as an immunosuppressive agent. O O

H2NCN N C NH2

Adefovir Gilead Sciences References: 1,7,8

9-[2-(Phosphonylmethoxy)ethyl]adenine, PMEA, GS 393. Principal target virus: HBV. Other activities: HIV-1, HIV-2, HCMV, HSV-1, HSV-2, FIV, SIV. Compound class: NtRTI (acyclic nucleoside phosphonate).

NH2 Used as its oral prodrug, adefovir dipivoxil, in the treatment of chronic HBV infections. N N

O N N HO P O OH

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Gilead Sciences Adefovir dipivoxil References: 1,9,10 Hepsera® 9-[2-[(Bis[pivaloyloxy)methyl]phosphonyl]methoxyethyl]adenine, GS 840, bis(POM)PMEA. Principal target virus: HBV. Other activities: HIV, FIV, SIV. NH2 Mode of action: Oral prodrug of the acyclic nucleoside H3C N phosphonate, adefovir. N CH3 Compound class: NtRTI. H3C O Clinical stage: Licensed. O N O N O P O Used for treatment of chronic HBV infections. O O O H3C CH3 H3C

Medivir, Presidio Pharmaceuticals References: 11–13

3′Fluoro-3′-deoxythymidine, MIV-310, FLT. Principal target virus: HIV-1. Other activities: HIV-2. Mode of action: Polymerase inhibitor. O Compound class: NRTI. Clinical stage: Phase IIb. CH3 HN This compound is a chain terminator. O N HO O

F

Genzyme AMD3100 References: 14–16 Mozobil™ 1,1′-[1,4-Phenylenebis-(methylene)]bis[1,4,8,ll-tetraazacyclotetradecane] octahydrochloride dihydrate, , JM 3100, SDZ, SID 791. Principal target virus: HIV-1. Other activities: HIV-2. Mode of action: CXCR4 antagonist. Compound class: Bicyclam. Clinical stage: In Phase II/III trials. NH NNHN Clinically being pursued as stem- mobilizer (that is, in patients with non-Hodgkin lymphoma and patients with multiple myeloma). This compound was formally developed NH HN 8 HCl NH HN by AnorMed. 2H2O

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Retroviruses.indd 77 28/7/08 13:47:31 Factfile: Retroviruses

Amprenavir Vertex Pharmaceuticals/ Agenerase®, Prozei® GlaxoSmithKline (GSK) References: 17–20

[(3S)-Oxolan-3-yl] N-[(2S,3R)-4-[(4-aminophenyl)sulfonyl-(2- ­methylpropyl)amino]-3-hydroxy-1-phenyl-butan-2-yl]carbamate, l4lW94, VX478. Principal target virus: HIV-1. Other activities: HIV-2. Compound class: Protease inhibitor. O O O O S Clinical stage: Licensed.

O N N Used for the treatment of HIV infections (AIDS). H OH CH3 NH2

CH3

Aplaviroc Ono Pharmaceutical, GlaxoSmithKline (GSK) References: 21–23

4-[4-[[1-Butyl-3-[(R)-cyclohexyl-hydroxy-methyl]-2,5-dioxo-1,4,9- triazaspiro[5.5]undec-9-yl]methyl]phenoxy]benzoic acid, 873140, GW-873140, ONO-4128, AK-602. Principal target virus: HIV-1. O Mode of action: CCR5 antagonist. Clinical stage: Phase III clinical trials. HO N N O This compound has been recently discontinued because of O possible hepatotoxicity. O N H OH

Apricitabine Avexa Ltd References: 24–26

(-)2′-Deoxy-3-oxa-4-thiocytidine, AVX754, BCH-10618, SPD754. Principal target virus: HIV-1. Other activities: HIV-2. Mode of action: DNA chain terminator. NH2 Compound class: NRTI. Clinical stage: Phase IIb/III trials. N Under clinical development for treatment of drug-resistant HIV-1 infection. N O HO S

O

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Bristol-Myers Squibb References: 27–29 Reyataz® Methyl N-[(1S)-1-[[[(2S,3S)-2-hydroxy-3-[[(2S)-2- (methoxycarbonylamino)-3,3-dimethyl-butanoyl]amino]-4-phenyl- butyl]-[(4-pyridin-2-ylphenyl)methyl]amino]carbamoyl]-2,2-dimethyl- propyl]carbamate, BMS-232632. Principal target virus: HIV-1. N Mode of action: Protease inhibitor. Clinical stage: Licensed.

O OH O H H N N N O O N N H H O O

University of North Carolina, Panacos References: 30–32

4-((1R,3aS,5aR,5bR,7aR,9S,11aR,11bR,13aR,13bR)-3a-carboxy- 1-isopropenyl-5a,5b,8,8,11a-pentamethyl-eicosahydrocyclopenta[a] chrysen-9-yl) ester, 3-O-(3′,3′-dimethylsuccinyl)-betulinic acid, 2,2- dimethyl-succinic acid, PA-457. Principal target virus: HIV-1. Mode of action: HIV-1 maturation (assembly). Clinical stage: Phase IIb clinical trial. H Bevirimat blocks HIV maturation by inhibiting the final step in HIV Gag . H COOH O H HOOC O H

Bristol-Myers Squibb BMS-378806 References: 33,34

1-[(2R)-4-Benzoyl-2-methyl-piperazin-1-yl]-2-(5-methoxy-2,9- diazabicyclo[4.3.0]nona-1,3,5,7-tetraen-7-yl)ethane-1,2-dione. Principal target virus: HIV-1. Mode of action: HIV-1 attachment inhibitor. Clinical stage: Phase I. O Development discontinued due to inadequate pharmacokinetics. OMe O N N

N O CH3 N H OMe

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Retroviruses.indd 79 28/7/08 13:47:33 Factfile: Retroviruses BMS-488043 Bristol-Myers Squibb References: 33,34

1-(4-Benzoylpiperazin-1-yl)-2-(5-methoxy-2,9-diazabicyclo[4.3.0] nona-1,3,5,7-tetraen-7-yl)ethane-1,2-dione. Principal target virus: HIV-1. Mode of action: HIV-1 attachment inhibitor. O Clinical stage: Phase IIa. Proof-of-concept established in HIV patients. Development OMe O N discontinued because of high-dose requirement. N

N O N H OMe

Calanolide A Sarawak Medichem Pharmaceuticals References: 35–37

(10R,3S,12S)-3,12-Dihydro-12-hydroxy-6,6,10,3-tetramethyl-4-propyl- 2H,6H,10H-benzo(1,2-b:3,4-b′:5,6-b′′)tripyran-2-one. Principal target virus: HIV-1. Other activities: HIV-2. Compound class: NNRTI. Clinical stage: Phase I/II dose escalation trials. O No recent data made available.

O O O

OH

Capravirine Pfizer References: 38

(5-(3,5-Dichlorophenyl)thio-4-isopropyl-1-(4-pyridyl)methyl-1H-imidazol- 2-ylmethyl carbamate, AG 1549, S-353. Principal target virus: HIV-1. Compound class: NNRTI. N Clinical stage: Phase II/III trials. No recent data available. This compound has been discontinued. O Cl S N O NH2 N H3C Cl CH3

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Bukwang, Eisai, Pharmasset Clevudine References: 39–41 Levovir® 1-(2-Deoxy-2-fluoro-β-l-arabinofuranosyl)-5-methyl uracil, l-FMAU. Principal target virus: HBV. Other activities: EBV. Mode of action: HBV DNA polymerase inhibitor. Compound class: Nucleoside analogue. O Clinical stage: Phase III. CH 3 HN

In clinical trials clevudine demonstrated sustained anti-HBV O N OH activity as well as normalization of the alanyl aminotransferase O level as much as 6 months after the discontinuation of the F drug. It has been approved for the treatment of chronic HBV infection in South Korea in November 2006 and is undergoing the Phase III trials in US and Europe. OH

RFS Pharma LLC DAPD References: 42–44 ® (–)-β-D-2,6-Diaminopurine dioxolane, AMDX. Principal target virus: HIV. Other activities: HBV. Mode of action: Inhibition of HIV-1 reverse transcriptase. Compound class: NRTI. NH2 Clinical stage: In Phase II trials for treatment of HIV. N N No recent data made available. NH2 N N HO O

O

Tibotec (Johnson & Johnson) References: 27,45,46 Prezista® [(1R,5S,6R)-2,8-Dioxabicyclo[3.3.0]oct-6-yl] N-[(2S,3R)-4-[(4- aminophenyl)sulfonyl-(2-methylpropyl)amino]-3-hydroxy-1-phenyl- butan-2-yl]carbamate, TMC-114. Principal target virus: HIV-1. Compound class: Protease inhibitor. Clinical stage: Licensed.

O O O O N N H OH S O O

NH2

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Retroviruses.indd 81 28/7/08 13:47:35 Factfile: Retroviruses DEBIO-025 Debio References: 47–49

Cylcosporin A analogue. Principal target virus: HIV and HCV. Compound class: Cyclophilin inhibitor. CH3 Clinical stage: Phase II for HCV infections.

H3C CH3 CH3 O HO H C 3 N C11 CH NC CH 3 1 O 3 C10 H C CH H3C O O 3 3 N HN H3C CH3 C2 O C9

H3C N N CH3 H C C O 3 3

C8 O H3C NH N CH C4 3 O C CH3 7 NH H3C HN CH3 H3C O N C5 O C6 CH3 H3C O H3C

CH3

Delavirdine Pharmacia & Upjohn References: 1,27,50,51 Rescriptor® 1-(5-Methanesulfonamido-1H-indol-2-yl-carbonyl)-4-[3-(1-methyl ethyl-amino)pyridinyl]piper-azine monomethane sulfonate, U-90152S. Principal target virus: HIV-1. Compound class: NNRTI. Clinical stage: Licensed. H3C Has been previously used for the treatment of HIV infection H C CH3 3 (AIDS). SO2 HN HN N N N N H O

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Retroviruses.indd 82 28/7/08 13:47:36 Factfile: Retroviruses Emory University, Pharmasset References: 52–55 Reverset® DPC-817, β-d-Fd4C, b-d-2′,3′-didehydro-2′,3′-dideoxy-5-fluorocytidine, DFC. Principal target virus: HIV-1. Other activities: HBV. Mode of action: Inhibitor of HIV reverse transcriptase and NH2 HBV polymerase. Compound class: NRTI. F Clinical stage: Phase II clinical trials. N

Dexelvucitabine could be useful in combination with O N ­lamivudine according to Hernandez-Santiago et al. [53]. HO O

Bristol-Myers Squibb References: 1,56,57 Videx®, Videx EC® 2′,3′-Dideoxyinosine, ddI. Principal target virus: HIV-1. Other activities: HIV-2. Compound class: NRTI. Clinical stage: Licensed. O Used for the treatment of HIV infections (AIDS). HN N

N N HO O

Bristol-Myers Squibb/Merck Efavirenz References: 58–60 Sustiva®/Stocrin® (–)6-Chloro-4-cyclopropylethynyl-4-trifluoromethyl-l,4-dihydro-2H-3, 1-benzoxazin-2-one, L-743,726, DMP-266. Principal target virus: HIV-1. Compound class: NNRTI. Clinical stage: Licensed.

Used for the treatment of HIV infections (AIDS). A single (oral) daily combination pill containing tenofovir disoproxil fumarate (Viread®), (Emtriva®) and efavirenz (Sustiva®) has F3C been has been approved. This combination is called Atripla®. Cl O

N O H

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Elvitegravir Gilead Sciences References: 61,62

6-[(3-Chloro-2-fluorophenyl)methyl]-1,4-dihydro-1-[(1S)-1-isopropyl- 2-hydroxyethyl]-7-methoxy-4-oxo-3-quinolinecarboxylic acid, GS-9137, JTK-303.

OH Principal target virus: HIV. H Mode of action: Inhibitor of integrase (strand transfer). Clinical stage: Phase II/III.

O N

OH

F O O

Cl

Elvucitabine Yale University, Achillion References: 27

b-l-2′,3′-Didehydro-2′,3′-dideoxy-5-fluorocytidine,β -l-Fd4C, ACH-126443. Principal target virus: HIV-1. Other activities: HBV. Compound class: NRTI. NH2 Clinical stage: Phase II clinical. F N No recent data made available.

O N HO

O

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Mitsubishi Kasei Corporation References: 63–65 Coactinon™ 6-Benzyl-1-(ethoxymethyl)-5-isopropyl-uracil, l-EBU, MKC-442. Principal target virus: HIV-1. Compound class: NNRTI. Clinical stage: Phase III trials.

Discontinued. This compound was formally developed by O CH3 Triangle Pharmaceuticals. HN CH3

O N

H3C O

Gilead Sciences Emtricitabine References: 1,66,67 Emtriva® (-)2′,3′-Dideoxy-5-fluoro-3′-thiacytidine, BW524W91, 5-fluoro-(-)-β-l- 2′,3′-dideoxy-3′-thiacytidine, (-)-FTC Principal target virus: HIV. Other activities: HBV. Compound class: NRTI. NH Clinical stage: Licensed. 2 F 5-Fluoro analogue of lamivudine. Used for the treatment N of HIV infections mostly in combination with tenofovir disoproxil fumarate (Viread®). This combination is referred to N O as Truvada®. A single (oral) daily combination pill contain- HO ing tenofovir disoproxil fumarate (Viread®), emtricitabine S (Emtriva®) and efavirenz (Sustiva®) has been approved: this combination is called Atripla®. O

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Retroviruses.indd 85 28/7/08 13:47:38 Factfile: Retroviruses Trimeris/Roche References: 1,68–70 Fuzeon® T-20, DP-178, YTSLIHSLIEESQNQQEKNEQELLELDKWASLWWWF. Principal target virus: HIV-1. Other activities: HIV-2. Mode of action: A 36 amino acid peptide that binds to HIV . Compound class: Fusion inhibitor. Clinical stage: Licensed.

O Used in the salvage of HIV infections (AIDS). Has to be administered subcutaneously twice daily. N H O H N 2 O NH NH HO HO 2 N H O NH O O O HO O H N HN HN H N O HN NH O O N H N H O O OH H N H N NH O O N H NH N N H O O HO H N 2 NH H N O O N H N H OH O O O H N OH H N O O N H O OH N H O O O H N O HO H N O O HO 2 N H NH N H O O O H N O NH HO O OH O O 2 O O N 2 N H 2 NH O H NH HN O O O NH NH NH O O O HN HN HN N O O 2 H N O O 2 H N 2 H

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Retroviruses.indd 86 28/7/08 13:47:38 Factfile: Retroviruses Bristol-Myers Squibb Entecavir References: 71–73 Baraclude® 2-Amino-9-[(1S,3R,4S)-4-hydroxy-3-(hydroxymethyl)-2-methyl- idenecyclopentyl]-3H-purin-6-one Principal target virus: HBV. Compound class: Nucleoside analogue. O Clinical stage: Licenced. N HN

N N H2N

CH2 HO

OH

Tibotec (Johnson & Johnson) References: 46,74,75

4-[6-Amino-5-bromo-2-[(4-cyanophenyl)amino]pyrimidin-4-yl] oxy-3, 5-dimethyl-benzonitrile, TMC-125, R-165335. Principal target virus: HIV-1. Compound class: NNRTI. N N Clinical stage: Licensed.

O N NH

N Br

NH2

Beecham Research Laboratories Ltd. Famciclovir References: 76–78 Famvir® Diacetyl 6-deoxy-9-(4-hydroxy-3-hydroxymethyl-but-1-yl)guanine, BRL 42810, FCV. Principal target virus: HSV-1, HSV-2, VZV. Other activities: EBV, HBV. N N Mode of action: Phosphorylated by herpes thymidine kinase then inhibits herpes DNA polymerase. N Clinical stage: Licensed. H2N N

Marketed by Novartis. The compound is an oral prodrug of O penciclovir; an acyclic guanosine derivative used for HSV-1, HSV-2 and VZV infections. H3C O

O

O CH3

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Retroviruses.indd 87 28/7/08 13:47:39 Factfile: Retroviruses Fialuridine Eli Lilly References: 79,80

1-2′-Deoxy-2′fluoro-1-b-d-arabinofuranosyl-5-iodouracil, FIAU, 2′-fluoro-5-iodo-ara-uracil. Principal target virus: HBV. Other activities: HSV-1, HSV-2. O Mode of action: Inhibits HBV DNA synthesis. I Compound class: Nucleoside analogue. HN Clinical stage: Withdrawn after Phase II trial.

O N Fialuridine results in severe liver toxicity. HO O F

OH

Fosamprenavir GlaxoSmithKline (GSK) References: 1,27,81,82 Lexiva®, Telzir® [(2R,3S)-1-[(4-Aminophenyl)sulfonyl-(2-methylpropyl)amino]-3-[[(3S)- oxolan-3-yl]oxycarbonylamino]-4-phenyl-butan-2-yl] oxyphosphonic acid, GW 433908, VX-175, phosphate. Principal target virus: HIV-1. Compound class: Protease inhibitor. Clinical stage: Licensed.

O O O O Used for the treatment of HIV infections (AIDS). S represents the prodrug of amprenavir. O N N H O CH3 NH2 O P OH HO CH3

Foscarnet Astra Zeneca References: 1,83,84 Foscavir® Trisodium carboxyphosphonate, trisodium phosphonoformate hexahydrate, sodium, trisodium phosphonoformate, phosphonoformic acid, PFA. Principal target virus: HCMV. Other activities: HSV-1, HSV-2, VZV, EBV, HHV-6, HIV. Mode of action: Analogue of inorganic pyrophosphate. Targets herpesvirus DNA polymerase at the pyrophosphate-binding site. O Compound class: Pyrophosphate analogue. OH Clinical stage: Licensed. PHO C OH O Foscarnet is often supplied as sodium salt. It is occasionally used for the treatment of HCMV retinitis, pneumonia, gastrointestinal and disseminated infections. Toxicity is well known, but it is among alternative compounds available to treat nucleoside-resistant HSV and VZV infections in immunocompromised patients.

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Retroviruses.indd 88 28/7/08 13:47:40 Factfile: Retroviruses GlaxoSmithKline (GSK) GW678248 References: 85

2-[4-Chloro-2-(3-chloro-5-cyano-benzoyl)phenoxy]-N-(2-methyl-4- sulfamoyl-phenyl)acetamide. Principal target virus: HIV-1. Compound class: NNRTI. Clinical stage: Phase II clinical. H N O O N O NH2 S O O

Cl Cl

Bristol-Myers Squibb Hydroxyurea References: 86,87 Hydrea® HU, . Principal target virus: HIV. Mode of action: Ribonucleotide reductase inhibitor. Clinical stage: Has been studied in Phase III trials as part of triple combination therapy. Not vigorously pursued.

Potentiates the action of some NRTIs, such as didanosine. O C HN NH2 OH

Nexell Pharmaceuticals Hypericin References: 88,89 VIMRxyn® 1,3,4,6,8,13-Hexahydroxy-10,11-dimethylphenanthrol[1,10,9,8-opqra] perylene-7,14-dione. Principal target virus: HIV-1. Other activities: HIV-2. OH O OH Clinical stage: Has been subject of Phase l/ll trials.

Naturally occurring compound. Multiple mechanisms of action. No longer considered for clinical use against HIV infections. HO CH3

HO CH3

OH O OH

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Retroviruses.indd 89 28/7/08 13:47:41 Factfile: Retroviruses Merck References: 90,91 Crixivan® (2S)-1-[(2S,4R)-2-Hydroxy-4-[[(1S,2R)-2-hydroxy-2,3-dihydro-1H- inden-1-yl]carbamoyl]-5-phenyl-pentyl]-4-(pyridin-3-ylmethyl)-N-tert- butyl-piperazine-2-carboxamide, MK-639, L-735,524. Principal target virus: HIV-1. Other activities: HIV-2. Compound class: Protease inhibitor. Clinical stage: Licensed. N OH H N N Used for the treatment of HIV infections (AIDS). N O O NH CH3 HO

H3C CH3

Lamivudine GlaxoSmithKline (GSK) References: 1,92,93 Epivir®, Zeffix® (–)-β-L-2′,3′-Dideoxy-3′-thiacytidine, 3TC, GR 109714X, (–)-BCH189. Principal target virus: HIV. Other activities: HBV. Compound class: NRTI. Clinical stage: Licensed. NH2 Used for the treatment of both HIV (AIDS) and HBV (chronic N hepatitis B) infections. Has been coformulated with zidovudine as Combivir®, with abacavir as Kivexa®, and with both N O zidovudine and abacavir as Trizivir®. HO S

O

Lodenosine US Bioscience References: 94–96

9-(2,3-Dideoxy-2-fluoro-β-threo-pentofuranosyl)adenine, FddA, 2′-β- fluoro-2′,3′-dideoxyadenosine. Principal target virus: HIV-1. Other activities: HIV-2. Compound class: NRTI. NH 2 Clinical stage: Phase I trials completed. Has been discontinued. N N 2′-β-Fluoro analogue of 2′,3′-dideoxyadenosine. This compound was originally discovered by the US National Cancer Institute. N N HO O F

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Retroviruses.indd 90 28/7/08 13:47:42 Factfile: Retroviruses Abbott Laboratories References: 1,97,98

(2S)-N-[(2S,4S,5S)-5-[[2-(2,6-Dimethylphenoxy)acetyl]amino]-4- hydroxy-1,6-diphenyl-hexan-2-yl]-3-methyl-2-(2-oxo-1,3-diazinan-1-yl) butanamide, ABT-378. Principal target virus: HIV-1. Other activities: HIV-2. Compound class: Protease inhibitor. Clinical stage: Licensed.

CH3 OH O Lopinavir is used for the treatment of HIV infections (AIDS) in H combination with at a 4:1 ratio (Kaletra®). O N N NH N H O O CH3 H3C CH3

Janssen Pharmaceutica References: 99,100

2-[(2-Acetyl-5-methyl-phenyl)amino]-2-(2,6-dichlorophenyl)acetamide, α-APA. Principal target virus: HIV-1. Compound class: NNRTI. Clinical stage: Discontinued after phase II/III clinical trials. CH3

O NH2 Cl

N H C Cl O CH3

Pfizer Inc References: 101,102 Selzentry® 4-Difluoro-N-[(1S)-3-[(1S,5R)-3-(3-methyl-5-propan-2-yl-1,2,4-triazol- 4-yl)-8-azabicyclo[3.2.1]oct-8-yl]-1-phenyl-propyl]cyclohexane-1- carboxamide. Principal target virus: HIV. Mode of action: Coreceptor CCR5 antagonist. Clinical stage: Licensed. F H Anti-HIV activity confined to CCR5-using HIV strains. F H N N N N N O H

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Retroviruses.indd 91 28/7/08 13:47:43 Factfile: Retroviruses MDL 28574 Marion Merrell Dow References: 103,104

6-O-Butanoylcastanospermine, MDL 28,574A. Principal target virus: HIV-1. Other activities: HIV-2. Mode of action: α-Glucosidase l inhibitor. Clinical stage: Phase II trials.

OH No further follow-up over the past years. H3C O OH

O N OH

MIV-160 Medivir, Mefuvir References: 105,106

(-)-cis-1-(5-Cyanopyridin-2-yl)-3-(4,7-difluoro-1,1a,2,7b-tetrahydro- cyclopropa[c]chromen-1-yl)-urea, MSR-216. Principal target virus: HIV-1. Mode of action: Reverse transcriptase inhibitor. Compound class: NNRTI. F Clinical stage: Preclinical. O H CN O

F H N N N H

MIV-210 Medivir, Hainan Noken Pharmaceutical References: 107–109

2′,3′-dideoxy-3′-fluoroguanosine prodrug, FLG prodrug, FddG prodrug. Principal target virus: HBV, HIV. Mode of action: Reverse transcriptase inhibitor. O Compound class: NRTI. Clinical stage: Phase II. N HN

N H2N N O O H H H2N C C O C C O O CH CH3 H3C CH3

F

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Agouron Pharmaceuticals/Pfizer References: 1,110,111 Viracept® (3S,4aS,8aS)-2-[(2R,3R)-2-Hydroxy-3-[(3-hydroxy-2-methyl-benzoyl) amino]-4-phenylsulfanyl-butyl]-N-tert-butyl-3,4,4a,5,6,7,8,8a-octahydro- 1H-isoquinoline-3-carboxamide, AG-1343. Principal target virus: HIV-1. Other activities: HIV-2. Compound class: Protease inhibitor. H 3C CH 3 Clinical stage: Licensed. CH 3 S O NH Used for the treatment of HIV infections (AIDS). CH 3 O HO •CH3SO2-OH N N H OH

Roxane Laboratories (Boehringer Ingelheim) Viramune® References: 112–114

1-Cyclopropyl-5,11-dihydro-4-methyl-6H-dipyrido [3,2-b:2′,3-e] [1,4] diazepin-6-one, BI-RG-587. Principal target virus: HIV-1. Compound class: NNRTI. O Clinical stage: Licensed. H3C HN Used for the treatment of HIV infections (AIDS), in combination with NRTIs. N N N

Medivir, Population Council PC 815 References: 115–117

(+)-(1S,2S)-N[cis-2-(6-fluoro-2-hydroxy-3-propionyl-phenyl)- cyclopropyl]-N′-[2-(5-cyanopyridyl)]urea, MIV-150, MSN-034, PETT-5. Principal target virus: HIV-1. Compound class: NNRTI. CN Clinical stage: Phase I. F O

Microbicide for vaginal use against HIV transmission. N N N H H OH

O

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Retroviruses.indd 93 28/7/08 13:47:45 Factfile: Retroviruses Penciclovir Beecham Research Laboratories Ltd. References: 118–120 Denavir®/Vectavir® (for 1% cream) 9-(4-Hydroxy-3-hydroxymethyl-but-1-yl)guanine, PCV, BRL 39123. Principal target virus: HSV-1, HSV-2. Other activities: VZV, EBV, HBV. Mode of action: Similar to acyclovir, but higher affinity for HSV O thymidine kinase and lower affinity for HSV DNA polymerase. Compound class: Acyclic nucleoside analogue. HN N Clinical stage: Licensed.

N Marketed by Novartis. Similar to acyclovir with similar H2N N resistance profile, but appears to have longer intracellular HO half life than acyclovir. A 1% cream (Vectavir®) is licensed for topical therapy for cutaneous HSV-1 infections (herpes labialis). The oral bioavailabilty is very low and the prodrug OH form, famciclovir, is among the first of the successful antiviral prodrugs. As famciclovir, it is used for VZV infections.

PRO 2000 Procept References: 121–123 PRO 2000/5 Naphthalene sulfonate polymer. Principal target virus: HIV-1, HIV-2. Other activities: HSV-1, HSV-2. Compound class: Sulfonated polyamide. Clinical stage: Phase II/III.

Microbicide (virucide) vaginal gel. CH2

SO2ONa 21

No generic name Emory University, Pharmasset References: 124–126 ® Racemic (±)FTC. Principal target virus: HIV-1. Other activities: HBV. Mode of action: Inhibitor of HIV reverse tra§nscriptase and NH2 HBV polymerase. Compound class: NRTI. F N Clinical stage: Phase II clinical trial.

O N HO S

O

94 © 2008 International Medical Press

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Merck References: 127,128 Isentress™ N-[2-[(4Z)-4-[[(4-fluorophenyl)methylamino]-hydroxymethylidene]- 1-methyl-5,6-dioxopyrimidin-2-yl]propan-2-yl]-5-methyl-1,3,4- oxadiazole-2-carboxamide, MK-0518. Principal target virus: HIV. Mode of action: Inhibitor of integrase (strand transfer). Clinical stage: Licensed. O OH F N N N H H N N O N O O

Tibotec Rilpivirine References: 129–131

4-((4-((4-((1E)-2-Cyanoethenyl)-2,6-dimethylphenyl)amino)-2-pyrimidinyl) amino)benzonitrile, TMC-278, R 278474. Principal target virus: HIV. Compound class: NNRTI. Clinical stage: Phase III.

Under clinical development. N N N

N N N H H

Abbott Laboratories Ritonavir References: 1,132,133 Norvir® 1,3-Thiazol-5-ylmethyl N-[(2R,3R,5R)-3-hydroxy-5-[[(2S)-3-methyl- 2-[[methyl-[(2-propan-2-yl-1,3-thiazol-4-yl)methyl]carbamoyl]amino] butanoyl]amino]-1,6-diphenyl-hexan-2-yl]carbamate, ABT-538. Principal target virus: HIV-1. Other activities: HIV-2. Compound class: Protease inhibitor. H3C Clinical stage: Licensed. CH3 O O H Used for the treatment of HIV infections (AIDS), now also N N N N O routinely used to boost the activity of other protease inhibitors. S H H N Ritonavir is used for the treatment of HIV infections (AIDS) in NCH3 O OH S combination with lopinavir at a 1:4 ratio (Kaletra®). H3C CH3

© 2008 International Medical Press 95

Retroviruses.indd 95 28/7/08 13:47:46 Factfile: Retroviruses Hoffman-La Roche References: 1,134,135 Invirase®, Fortovase® (2S)-N-[(2R,3R)-4-[(3S,4aR,8aS)-3-(Tert-butylcarbamoyl)-3, 4,4a,5,6,7,8,8a-octahydro-1H-isoquinolin-2-yl]-3-hydroxy-1- phenylbutan-2-yl]-2-(quinoline-2-carbonylamino)butanediamide methane sulfonate, Ro-318959. Principal target virus: HIV-1. Other activities: HIV-2. Compound class: Protease inhibitor. O H Clinical stage: Licensed. N N N N H Available for the treatment of HIV infections (AIDS) in both O OH hard gel (Invirase®) and soft gel (Fortovase®) formulations. CH3S02-OH O O NH2 CH3

H3C CH3

Stavudine Bristol-Myers Squibb References: 24,136,137 Zerit® 2′,3′-Didehydro-2′,3′-dideoxythymidine, d4T, 3′-deoxy-2′-thymidinene. Principal target virus: HIV-1. Other activities: HIV-2. Compound class: NRTI. O Clinical stage: Licensed.

CH3 Used for the treatment of HIV infections (AIDS). HN

O N HO O

T-1249 Trimeris/Roche References: 138,139

Longer version of T-20. Principal target virus: HIV-1. Other activities: HIV-2. Mode of action: A 39 amino-acid peptide that binds to HIV gp41. Clinical stage: Phase I/II trials scheduled.

Decision taken not to continue development.

Ac-WQEWEQKITALLEQAQIQQEKNEYELQKLDKWASLWEWF-NH2

96 © 2008 International Medical Press

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Idenix/Novartis Telbivudine References: 28,140,141 Tyzeka™ 1-((2S,4R,5S)-4-hydroxy-5-hydroxymethyltetrahydrofurano-2-yl)- 5-methyl-1H-pyrimidine-2,4-dione 1-(2-deoxy-β-l-ribofuranosyl)-5- methyluracil, β-l-thymidine, b-l-2’-deoxythymidine, l-dT. Principal target virus: HBV. Other activities: HSV-1, HSV-2. O Compound class: l-Nucleoside analogue. CH3 Clinical stage: Licensed. HN

The compound is used for the treatment of chronic hepatitis B O N infections. OH O

OH

Gilead Sciences Tenofovir References: 142–144

(R)-9-(2-Phosphonylmethoxypropyl)adenine, PMPA, GS-4331-05. Principal target virus: HIV-1, HIV-2. Other activities: HBV. Compound class: NtRTI (acyclic nucleoside phosphonate). NH Used as its oral prodrug, tenofovir disoproxil fumarate, for the 2 treatment of HIV infections (AIDS). N N

O N N HO P O OH CH3

Gilead Sciences Tenofovir disoproxil References: 1,59,145,146

9-[2-(R)-[Bis2-isopropoxycarbonyloxymethyl]2-phosphonyl] methoxy- fumarate propyl]adenine fumarate, bis(isopropoxycarbonyloxymethyl)-PMPA, bis(POC)PMPA, GS-4331. Viread® Principal target virus: HIV-1, HIV-2. Other activities: HBV. NH Mode of action: Oral prodrug of the acyclic nucleoside 2 phosphonate, tenofovir. N Compound class: NtRTI (acyclic nucleoside phosphonate). N Clinical stage: Licensed. (CH3)2CH O O N Used for the treatment of HIV infections (AIDS). Used for H2 N the treatment of HIV infections alone or in combination with O C O O emtricitabine (Emtriva®). This combination is referred to as ® P O Truvada . A single (oral) daily combination pill of tenofovir H2 disoproxil fumarate (Viread®), emtricitabine (Emtriva®) and O C O ® efavirenz (Sustiva ) has been made available: this combination CH3 is called Atripla®. New drug application has also been filed for O Viread® for treatment of HBV infections. At present, licensed O for the treatment of chronic hepatitis B in New Zealand, Turkey (CH3)2CH and the European Union.

© 2008 International Medical Press 97

Retroviruses.indd 97 28/7/08 13:47:48 Factfile: Retroviruses Boehringer Ingelheim References: 27,147,148 Aptivus® N-[3-[(1R)-1-[(6R)-2-Hydroxy-4-oxo-6-phenethyl-6-propyl-5H- pyran-3-yl]propyl]phenyl]-5-(trifluoromethyl)pyridine-2-sulfonamide, PNU-140690. Principal target virus: HIV-1. Other activities: HIV-2. Compound class: Protease inhibitor (non-peptidomimetic). Clinical stage: Licensed. O O O O Used for the treatment of HIV infections (AIDS). S N H OH N F F F

Tivirapine Janssen Pharmaceutica References: 149–151

(+)-5(S)-4,5,6,7-Tetrahydro-8-chloro-5-methyl-6-(3-methyl-2-butenyl) imidazo-[4,5,1-jk]-[1,4]benzodiazepin-2(1H)-thione, R86183, 8-chloro-TIBO. Principal target virus: HIV-1. Compound class: NNRTI. Cl Clinical stage: Phase I trial.

H3C Not further developed for treatment of HIV infections (AIDS). H3C N

NNH H3C

S

Trovirdine Medivir References: 150,152

3-(5-Bromopyridin-2-yl)-1-(2-pyridin-2-ylethyl)thiourea hydrochloride, LY-300046 HCl. Principal target virus: HIV-1. Compound class: NNRTI.

No recent data made available. HCl Br N S

N N N H H

98 © 2008 International Medical Press

Retroviruses.indd 98 28/7/08 13:47:49 Factfile: Retroviruses Medivir, Epiphany Bioscience Valomaciclovir stearate References: 153–155

[l-valine, (3R)-3-[(2-amino-1,6-dihydro-6-oxo-9H-purin-9-yl)methyl]- 4-[(1-oxooctadecyl)oxy]butyl ester], H2G prodrug, MIV-606, EPB-348, 2HM‑HBG prodrug. O Principal target virus: VZV. Other activities: HHV-6, HSV-1, HSV-2, EBV, HIV-1, HIV-2. N Mode of action: DNA polymerase inhibitor. NH Compound class: Nucleoside analogue. O N Clinical stage: Phase IIb. N NH2

Valomaciclovir stearate is a prodrug of H2G, it is rapidly (CH2)16CH3 O converted to H2G.

NH2 O

O

Idenix/Novartis Valtorcitabine References: 28,140,156

3′-Val-l-dC, 3′-Valine ester of β-deoxycytidine. Principal target virus: HBV. Mode of action: Prodrug of l-dC (torcitabine). NH2 Compound class: l-nucleoside analogue (prodrug). Clinical stage: Phase II. N Likely to be used in combination with telbivudine. O N OH O

NH2

O CH3

O CH3

Schering-Plough Vicriviroc References: 157–159

(4,6-dimethylpyrimidin-5-yl)-[4-[(3S)-4-[(1R)-2-methoxy-1-[4- (trifluoromethyl)phenyl]ethyl]-3-methyl-piperazin-1-yl]-4-methyl-1- piperidyl]methanone, SCH-D, SCH-417690. Principal target virus: HIV-1. Compound class: Coreceptor CCR5 antagonist. O Clinical stage: Phase II clinical trial.

Anti-HIV activity confined to CCR5-using HIV strains. N F N N F F N N

O

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Retroviruses.indd 99 28/7/08 13:47:50 Factfile: Retroviruses Hoffman-La Roche References: 1,160,161 Hivid® 4-Amino-1-β-d-2′,3′-dideoxyribofuranosyl-2-(1H)-pyrimidinone, dideoxycytidine, ddC. Principal target virus: HIV-1. Other activities: HIV-2. NH Compound class: NRTI. 2 Clinical stage: Licensed.

N Used for the treatment of HIV infections (AIDS), but infrequently prescribed. O N HO O

Zidovudine GlaxoSmithKline (GSK) References: 1,162,163 Retrovir® 3′-Azido-2′,3′-dideoxythymidine, Azidothymidine, ZDV, AZT. Principal target virus: HIV-1. Other activities: HIV-2. O Compound class: NRTI. Clinical stage: Licensed. CH3 HN Used (as first NRTI) for the treatment of HIV infections (AIDS). Has been coformulated with lamivudine as Combivir®, and with O N both lamivudine and abacavir as Trizivir®. HO O

N3

100 © 2008 International Medical Press

Retroviruses.indd 100 28/7/08 13:47:51 Factfile 13. Katlama C, Ghosn J, Tubiana R, et al. MIV-310 reduces Acknowledgements HIV viral load in patients failing multiple antiretroviral therapy: results from a 4-week phase II study. AIDS 2004; 18:1299–1304. The authors would like to acknowledge the following 14. De Clercq E, Yamamoto N, Pauwels R, et al. Highly potent individuals for contributing information and their and selective inhibition of human immunodeficiency virus type 1 by the bicyclam derivative JM3100. Antimicrob time in order to help us compile the FactFile: Robert Agents Chemother 1994; 38:668–674. Buckheit, David Chu, Susan Cox, Bo Öberg, Michael 15. Donzella GA, Schols D, Lin SW, et al. AMD3100, a small Otto, Raymond F Schinazi, Anthony Vere Hodge and molecule inhibitor of HIV-1 entry via the CXCR4 co- . Nat Med 1998; 4:72–77. Ze-Qe Xu. 16. De Clercq E. The bicyclam AMD3100 story. Nat Rev Drug Discov 2003; 2:581–587. Disclosure statement 17. Kim EE, Baker CT, Dwyer MD, et al. Crystal structure of HIV-1 protease in complex with VX-478, a potent and orally bioavailable inhibitor of the enzyme. J Am Chem Soc EDC is co-inventor of adefovir and tenofovir. For com- 1995; 117:1181–1182. pounds metioned herein HJF has no conflicts of interest. 18. Adkins JC, Faulds D. Amprenavir. Drugs 1998; 55:837–842. 19. Pham PA, Hendrix CW, Barditch-Crovo P, et al. Amprenavir and lopinavir pharmacokinetics following coadministration Disclaimer of amprenavir or fosamprenavir with lopinavir/ritonavir, with or without efavirenz. Antivir Ther 2007; 12:963–969. The authors declare that the second edition of the cur- 20. Crane HM, Kestenbaum B, Harrington RD, Kitahata MM. Amprenavir and didanosine are associated with declining rent antiviral agent FactFile is accurate and up-to-date kidney function among patients receiving tenofovir. AIDS to the best of their knowledge. The authors are happy 2007; 21:1431–1439. 21. 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