1 Outlook of the Antiviral Drug Era, Now More Than 50 - Wiley-VCH

28 Pages·2011·0.46 MB·English

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OutlookoftheAntiviralDrugEra,NowMoreThan50YearsAfter
Description of the First Antiviral Drug
ErikDeClercq
1.1
Introduction:ThePrehistory
More than 50 years ago, the synthesis of IDU (iododeoxyuridine), a thymidine
analogue,wasdescribedbyPrusoff[1].Thiscompoundwouldlaterbecomethefirst
antiviraldrugtobelicensedfor(topical)useinthetreatmentofherpessimplexvirus
(HSV)infectionsoftheeye.Inthissense,theadventofIDUmarkedthebirthofthe
antiviraldrugera.Therearenowabout50licensedantiviralcompounds,halfofthem
areusedforthetreatmentofAIDS,ofwhichtheviraloriginwasfirstrecognized27
years ago [2, 3] (2008 Nobel Prize for Medicine or Physiology was awarded to
Fran¸coiseBarr(cid:1)e-SinoussiandLucMontagnierfortheirdiscoveryofhumanimmu-
nodeficiency virusand toHarald zurHausen fordemonstrating thelinkbetween
humanpapillomavirus(HPV)andcervicalcancer).
WasIDUtrulythefirstantiviral?Inretrospect,theantiviralchemotherapyerahad
aratherslowandunremarkablestart.Thefirstcompoundsquotedtohaveantiviral
activity(againstvacciniavirus)werethethiosemicarbazones[4,5].Thesecompounds
werealsofoundeffectiveagainstvacciniavirusinfectioninmiceandrabbits[6–8],
and one of the thiosemicarbazones, that is, N-methylisatin-b-thiosemicarbazone,
even entered clinical studies for the prophylaxis of smallpox [9] just when the
smallpox vaccination took over and made any further attempts to develop an
antipoxvirusdrugapparentlysuperfluous.
Thencamethebenzimidazolederivativesasinhibitorsofinfluenzavirusmulti-
plication [10, 11], but despite the reported effectiveness of the 5,6-dichloro-1-b-D-
ribofuranosylbenzimidazole(DRB)[10,11]againstinfluenzavirusmultiplication,it
was not pursued further as a potential anti-influenza virus agent. Another benz-
imidazole derivative, 2-(1-hydroxybenzyl)benzimidazole (HBB), was found active
againstthemultiplicationofpoliovirus(andotherenteroviruses)[12–14],butwith
thesuccessfulimplementationofthepoliovirusvaccine,justaswehadwitnessedfor
smallpox,interestindevelopinganantiviraldrugforpoliovirusinfectionsvanished.
IDU,soontobefollowedbyTFT(trifluorothymidine),couldbeconsideredasthe
third,andsuccessful,attempttoheraldtheantiviralchemotherapyera.IDUwasfirst
AntiviralDrugStrategies,FirstEdition.EditedbyErikDeClercq.
(cid:1)2011Wiley-VCHVerlagGmbH&Co.KGaA.Published2011byWiley-VCHVerlagGmbH&Co.KGaA.
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2 1 OutlookoftheAntiviralDrugEra
consideredasapotentialantitumoragent[15]beforeitwasshownbyHerrmanntobe
activeagainstHSVandvacciniavirus[16].ThatIDUandTFTfinallybecameantiviral
drugsforthetopicaltreatmentofHSVeyeinfections,inparticularHSVkeratitis,is
duetothepioneeringworkofKaufman[17,18].
1.2
KeyEventsinAntiviralDrugDevelopment
Table1.1presentsthekeyeventsinantiviraldrugdiscovery,1959beingtheyearwhen
IDUwasfirstdescribed[1].Ribavirinwasthefirstlowmolecularweightcompound
described as a broad-spectrum antiviral agent (in 1972) by Sidwell et al. [19]. The
combinationofribavirinwith(pegylated)interferon-ahasnowbecomeastandard
treatment[20]forpatientswithchronichepatitisC.Thatvirusinfectionscouldbe
specificallytackled,withoutharmtothehostcell,washeraldedbytheadvent(in1977)
of acyclovir [21, 22], which is today still considered as the gold standard for the
treatmentofHSVinfections.TwoyearsafterthediscoveryofHIV,in1985,thefirst
antiretrovirus agent (to become a drug 2 years later), AZT (zidovudine) was
described[23],andthisopenedthesearchfor,anddevelopmentof,awealthofnew
20,30-dideoxynucleosideanalogues,nowcollectivelyreferredtoasnucleosidereverse
transcriptaseinhibitors(NRTIs).
In1986,wedescribedthefirstofanewclassofbroad-spectrumanti-DNAvirus
agents [24], namely, acyclic nucleoside phosphonates, several of which are active
against the HIV and HBV reverse transcriptase and, therefore, referred to as
nucleotide reverse transcriptase inhibitors (NtRTIs). Then followed in December
1989 and 1990 the description of a new concept for inhibiting the HIV-1 reverse
transcriptasebynonnucleosideanalogues(i.e.,HEPT[25,26]andTIBO[27]),giving
risetoastillgrowingclassofantiviraldrugs,thenonnucleosidereversetranscriptase
inhibitors(NNRTIs).Withsaquinavir,theyear1990markedthebirthoftherational
designofHIVproteaseinhibitors(HIVPIs),which,inthemeantime,hasyielded10
licenseddrugs.
In 1992, we described an unusual class of compounds, the bicyclams as HIV
inhibitorsinteractingwithaviraluncoatingevent[28].Thesecompounds(prototype:
AMD3100)wouldbe,lateron,showntoactasCXCR4antagonists.Togetherwiththe
CCR5antagonists(theonlylicensedanti-HIVdrugofthisclassofcompoundsbeing
maraviroc),CXCR4andCCR5antagonistscanbeconsideredcoreceptorinhibitors
(CRIs),targetedatthecoreceptorusageofX4andR5HIVstrains,respectively.The
year1993markedthedescriptionoftwototallydifferentstrategicoptions:(i)thatof
DP-178, which later on would become known as enfuvirtide as an HIV fusion
inhibitor (FI) [29] and (ii) that of 4-guanidino-Neu5Ac2en, which later on would
becomeknownaszanamivirasaneuraminidase-basedinhibitor(NAI)ofinfluenza
virus replication [30]. Then followed in 1998 the seminal observation that HSV
replicationcouldbeinhibitedattheDNAhelicase–primaselevelbya2-aminothiazole
(T157602)[31]thatwouldlatergiveimpetustothedevelopmentofhelicase–primase
inhibitors(HPIs)aspotentialanti-HSVdrugs.
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1.2 KeyEventsinAntiviralDrugDevelopment 3
described. (INIs)Elvitegravir Raltegravir L-870812 (Poxvirus L-870810 (HCV PIs)inhibitors) Boceprevir CI-1033 L-731988 Gleevec Telaprevir Diketo acids ST-246 Ciluprevir 200020032005 1998 2000 2003 ′C 2--methyl T157602 VP32947 nucleosides BILS 179BS Thiophene, Valopicitabine ′BAY 57-1293 Thiadiazine, 4-Azidocytidine (NRRIs(HPIsImidazopyridine ))derivatives GS-327073 (NNRRIs) NRRIs: nucleoside RNA replicase inhibitors NNRRIs: nonnucleoside RNA replicase inhibitors
first
ery:yearwhenkeycompoundswere (HIV PIs)Darunavir Tipranavir Fosamprenavir Atazanavir Lopinavir Amprenavir (NAIsNelfinavir )Indinavir Peramivir Ritonavir Oseltamivir Saquinavir Zanamivir 19901993 199219891993(1990) HEPT Bicyclams Enfuvirtide TIBO (FIs)CXCR4 Nevirapine Antagonists: Delavirdine AMD3100 CCR5 Efavirenz Etravirine antagonists: Dapivirine Maraviroc Aplaviroc Rilpivirine (NNRTIs)Vicriviroc (CRIs) FIs: fusion inhibitors INIs: integrase inhibitors NAIs: neuraminidase inhibitors HPIs: helicase–primase inhibitors HCV PIs: HCV protease inhibitors
Milestonesinantiviraldrugdiscovble1.1 (NtRTIs)Tenofovir Adefovir Cidofovir HPMPA 1986 1972 197719851959 AZT Ribavirin IDU Acyclovir Ganciclovir ddI TFT ddC BVDU Penciclovir Valaciclovir d4T BCNAs Famciclovir 3TC Valganciclovir ABC (-)FTC (NRTIs) NRTIs: nucleoside reverse transcriptase inhibitors NtRTIs: nucleotide reverse transcriptase inhibitors NNRTIs: nonnucleoside reverse transcriptase inhibitors HIV PIs: HIV protease inhibitors CRIs: coreceptor inhibitors
a
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Althoughconsideredanattractivetargetfortwodecadesorso,theHIVintegrase
becamearealistictargetonlywhenHazudaetal.[32]demonstratedin2000ittobe
inhibitedbytheso-calleddiketoacids,whichhaveyieldedoneintegraseinhibitor
(INI)thathasalreadybeenformallyapproved(raltegravir)andanotheroneunder
development (elvitegravir). Also described in 2000 was a pestivirus inhibitor
(VP32947) [33] that hallmarked the search for inhibitors targeted at the RNA-
dependentRNApolymerase(RdRp)ofnotonlypestivirusesbutalsohepaciviruses
(nonnucleoside RNA replicase inhibitors (NNRRIs)). In 2003, Lamarre et al.
published their pioneering observation that hepatitis C virus (HCV) replication
could be inhibited by ciluprevir [34], which (although the compound itself was
not further developed) generated the search for other HCV PIs. Also in 2003,
Migliaccio et al. [35] reported that 20-C-methyl-substituted ribonucleosides were
inhibitorytothereplicationofHCVandotherflavivirusesbyactingasnonobligate
chainterminators,thusincitingthesearchfornucleosideRNAreplicaseinhibitors
(NRRIs).
While,sincethedaysofmethisazone,interestindevelopingantiviralsforpoxvirus
infections(i.e.,smallpox)died,theadventin2005ofST-246testifiestotherenewed
interestinthisarea[36],andthisisfurtherdemonstratedbytheobservationsthat
poxvirus infections can be successfully suppressed through inhibitors of tyrosine
kinases(Gleevec[37]andCI-1033[38]).
1.3
AntiviralDrugs:CurrentStateoftheArt
Mostoftheantiviralagentsthathavebeenapproved,andareusedinthetreatmentof
virus infections,are targeted at HIV,HBV,HCV,influenzavirus,HSV, and other
herpesvirusessuchasvaricellazostervirus(VZV)andcytomegalovirus(CMV).More
compoundsforthetreatmentofHIV,HBV,HCV,HSV,VZV,CMV,andinfluenza
virusandseveralotherviralinfections,forexample,poxvirus(e.g.,variola,vaccinia,
andmonkeypox),respiratorysyncytialvirus,hemorrhagicfevervirus(e.g.,Lassa,Rift
Valley,Ebola,yellowfever,anddengue),andenterovirus(e.g.,polio,Coxsackie,and
Echo),eitherareinclinicalorpreclinicaldevelopmentorstillhavetobedeveloped.
TheantiviralcompoundsthathavebeenapprovedbytheUSFDA(FoodandDrug
Administration)arelistedinTable1.2.
1.4
AntiviralDrugsActiveagainstHerpesviruses(i.e.,HSV,VZV,andsoon)
Starting from IDU and TFT, many more 5-substituted 20-deoxyuridines were
synthesized [39], the most prominent antiviral drug of this class of compounds
being(E)-5-(2-bromovinyl)-20-deoxyuridine(BVDU)[40].Althoughselectivelyactive
against both HSV-1 and VZV, BVDU has been developed specifically for the
treatmentofVZVinfections(i.e.,herpeszoster)[41].
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1.4 AntiviralDrugsActiveagainstHerpesviruses(i.e.,HSV,VZV,andsoon) 5
Table1.2 AntiviraldrugsapprovedbytheUSFDA.
Registeredbrandname Genericname Manufacturer
Anti-HIVcompounds
Nucleosidereversetranscriptaseinhibitors
Retrovir Zidovudine(AZT) GlaxoSmithKline
Videx(cid:3),Videx(cid:3)EC Didanosine(ddI) Bristol–MyersSquibb
Hivid(cid:3) Zalcitabine(ddC) Roche
Zerit(cid:3) Stavudine(d4T) Bristol–MyersSquibb
Epivir(cid:3),Zeffix(cid:3) Lamivudine(3TC) GlaxoSmithKline
Ziagen(cid:3) Abacavir(ABC) GlaxoSmithKline
Emtriva(cid:3) Emtricitabine(((cid:2))FTC) GileadSciences
Combivir(cid:3) Lamivudineþzidovudine GlaxoSmithKline
Trizivir(cid:3) Abacavirþlamivudineþ GlaxoSmithKline
zidovudine
Epzicom(cid:3) Abacavirþlamivudine GlaxoSmithKline
Nucleotidereversetranscriptaseinhibitors
Viread(cid:3) Tenofovirdisoproxilfumarate GileadSciences
Truvada(cid:3) Tenofovirdisoproxil GileadSciences
fumarateþemtricitabine
Atripla(cid:3) Tenofovirdisoproxil GileadSciencesand
fumarateþ Bristol–MyersSquibb
emtricitabineþefavirenz
Nonnucleosidereversetranscriptaseinhibitors
Viramune(cid:3) Nevirapine BoehringerIngelheim
Rescriptor(cid:3) Delavirdine Pfizer
Sustiva(cid:3),Stocrin(cid:3) Efavirenz Bristol–MyersSquibb
Intelence(cid:3) Etravirine Tibotec
Proteaseinhibitors
Fortovase(cid:3) Saquinavir Roche
Norvir(cid:3) Ritonavir Abbott
Crixivan(cid:3) Indinavir Merck
Viracept(cid:3) Nelfinavir Pfizer
Agenerase(cid:3),Prozei(cid:3) Amprenavir GlaxoSmithKline
Kaletra(cid:3) Lopinavirþritonavir Abbott
Reyataz(cid:3) Atazanavir Bristol–MyersSquibb
Lexiva(cid:3) Fosamprenavir GlaxoSmithKline
Aptivus(cid:3) Tipranavir BoehringerIngelheim
Prezista(cid:3) Darunavir Tibotec
Viralentryinhibitors
Coreceptorinhibitors
Selzentry(cid:3),Celsentri(cid:3) Maraviroc Pfizer
Fusioninhibitors
Fuzeon(cid:3) Enfuvirtide(T-20) Roche
(Continued)
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Table1.2 (Continued)
Registeredbrandname Genericname Manufacturer
Integraseinhibitors
Isentress(cid:3) Raltegravir Merck
Anti-HBVcompounds
Epivir(cid:3),Zeffix(cid:3) Lamivudine(3TC) GlaxoSmithKline
Hepsera(cid:3) Adefovirdipivoxil GileadSciences
Baraclude(cid:3) Entecavir Bristol–MyersSquibb
Tyzeka(cid:3),Sebivo(cid:3) Telbivudine IdenixPharmaceuticals
Viread(cid:3) Tenofovirdisoproxilfumarate GileadSciences
IntronA(cid:3) Interferon-a-2b Schering-Plough
Pegasys(cid:3) Pegylatedinterferon-a-2a Roche
Antiherpesviruscompounds
HSVandVZVinhibitors
Zovirax(cid:3) Acyclovir(ACV) GlaxoSmithKline
Zelitrex(cid:3),Valtrex(cid:3) Valaciclovir(VACV) GlaxoSmithKline
Denavir(cid:3),Vectavir(cid:3) Penciclovir(PCV) Novartis
Famvir(cid:3) Famciclovir(FCV) Novartis
Herpid(cid:3),Stoxil(cid:3),Idoxene(cid:3), Idoxuridine(IDU,IUdR) YaleUniversity
Virudox(cid:3)
Viroptic(cid:3) Trifluridine(TFT) KingPharmaceuticals
Zostex(cid:3),Brivirac(cid:3),Zerpex(cid:3) Brivudin(BVDU)a BerlinChemie/Menarini
CMVinhibitors
Cymevene(cid:3),Cytovene(cid:3) Ganciclovir(GCV) Roche
Valcyte(cid:3) Valganciclovir(VGCV) Roche
Foscavir(cid:3) Foscarnet AstraZeneca
Vistide(cid:3) Cidofovir(CDV) Pfizer
Vitravene(cid:3) Fomivirsen Novartis
Anti-influenzaviruscompounds
Symmetrel(cid:3),Mantadix(cid:3), Amantadine EndoPharmaceuticals
Amantan(cid:3)
Flumadine(cid:3) Rimantadine ForestLaboratories
Relenza(cid:3) Zanamivir GlaxoSmithKline
Tamiflu(cid:3) Oseltamivir Roche
Virazole(cid:3),Virazid(cid:3),Viramid(cid:3) Ribavirin ValeantPharmaceuticals
Anti-HCVcompounds
Rebetol(cid:3) Ribavirin Schering-Plough
Copegus(cid:3) Ribavirin Roche
Pegasys(cid:3) Pegylatedinterferon-a-2a Roche
RoferonA(cid:3) Interferon-a-2a Roche
IntronA(cid:3) Interferon-a-2b Schering-Plough
PEG-Intron(cid:3) Pegylatedinterferon-a-2b Schering-Plough
Rebetron(cid:3) Interferon-a-2bþribavirin Schering-Plough
a)NotformallyapprovedbytheUSFDA.
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1.4 AntiviralDrugsActiveagainstHerpesviruses(i.e.,HSV,VZV,andsoon) 7
BVDUowesitsantiviralselectivitytoaspecificphosphorylationbytheHSV-1-and
VZV-encoded thymidine kinase, just as acyclovir does, but compared to acyclovir,
BVDU is a much more potent inhibitor of VZV replication. If BVDU is further
convertedtoabicyclicfurano[2,3-d]pyrimidinenucleosideanalogue(BCNA)carrying
an aliphaticside chain interrupted bya phenylmoiety [42,43], asinCf1743, the
compoundbecomesexquisitelyandexclusivelyactiveagainstVZV.
AlthoughBVDUandacyclovirbelong,respectively,tothepyrimidineandpurine
nucleoside analogues, they share, structurally, the same carboxamide pharmaco-
phore(Figure1.1),whichmayexplainwhytheyarebothspecificallyrecognizedas
substratebytheHSV-andVZV-encodedthymidinekinases.Thesamepharmaco-
phore is found in other acyclic guanosine analogues such as ganciclovir and
Br
O
CH
5 11
HN
O N
HO
O O
BVDU N
OH
O N
O
HO
O
R
HN
BCNA
Cf 1743
O N OH
HO
O
R = I : IDU
= CH3 : TFT
OH
O O O
N N N
HN HN HN
2
N
N HN N N HN N N
2 2
HO HO HO
O O X
Acyclovir
HO
HO OH
Ribavirin Ganciclovir (X = O)
Penciclovir (X = CH)
2
Figure1.1 Pharmacophoresinantiherpesvirusagents.
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Cl
N
H2N
S
T157602
O
H CH3
N
N
N O N
N O N SO2NH2
H2N CH3 N S
S CH3
BILS 179 BS BAY 57-1293
Figure1.1 (Continued)
penciclovir, again explaining the specificity of these compounds against HSVand
VZV.Remarkably,thesamepharmacophoreisalsofoundinribavirin,whichwas
describedasabroad-spectrumantiviralagent,5yearsbeforeacyclovirwasreported
(seeTable1.1),butinthecaseofribavirin,thepresenceoftheribofuranosylmoiety
primarily directs its antiviral activity spectrum toward RNA viruses due to an
inhibitoryactionattheleveloftheIMPdehydrogenase[44–46].
WhileBVDUandacyclovirinteractintheiractivetriphosphateformwiththeviral
DNApolymerase,thefirstphosphorylationstepbytheviralthymidinekinaserequired
onlytoinitiatetheactivationprocess,theHPIsseemtobedirectlytargetedattheHSV
helicase–primase UL5–UL8–UL52 complex [47]. The first HPI reported to inhibit
HSVreplicationviainteractionwiththehelicasecomponentofthiscomplex[31]was
the2-aminothiazoleT-157602.TheHPIsthatweresubsequentlydescribedandalso
foundtobemoreeffectivethanacyclovirandfamcicloviragainstHSVinfectionsin
murinemodelsofHSV-1andHSV-2infection[48–51],namely,BILS179BSandBAY
57-1293,arealsobuiltuponthe2-aminothiazolescaffold(Figure1.1).HPIsrepresent
an exciting new avenue in the development of antivirals active against herpes-
viruses [47], but whether they represent an alternative (or additional) strategy to
acyclovir (and acyclic guanosine analogues in general) will depend on their exact
spectrum of antiviral activity, whether or not encompassing VZV (an issue that
presently can only be speculated upon), and the readiness by which they elicit
resistancemutations[52,53](anissuethatneedscontinuedvigilance).
1.5
AntiviralDrugsActiveagainstRetroviruses(HIV)
The best known class of the antiretroviral agentsis that of the nucleoside reverse
transcriptaseinhibitors,nowcontainingsevenmembers–zidovudine,didanosine,
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1.5 AntiviralDrugsActiveagainstRetroviruses(HIV) 9
zalcitabine, stavudine, lamivudine, abacavir, and emtricitabine – that are on the
market [54]. What all these compounds have in common is that they are 20,30-
dideoxynucleosideanalogues(Figure1.2,NRTIs),whichthroughtheabsenceofa30-
hydroxylgroupinevitablyactaschainterminatorsatthereversetranscriptaselevel.
The last three of the series, namely, lamivudine (3TC, originally described as its
racemic form, BCH-189) [55], abacavir (1592 U89) [56], and emtricitabine (((cid:2))
NRTIs
O O NH2
CH3 CH3 R
HN HN N
O N O N O N
HO HO
O O
HO S
O
N3
AZT d4T R = H : 3TC
(Zidovudine) (Stavudine) (Lamivudine)
R = F : (-)FTC
(Emtricitabine)
NtRTIs
NH2 NH2
N N
N N
N N N N
HO O HO O
P O P O
HO HO
CH3
PMEA (R)-PMPA
(Adefovir) (Tenofovir)
NNRTIs
P95 Y318 N N N
W229 1.234
1.100 H235 N
P236
Wing I Wing II K101
F227
K103
O N NH
Y181 V106
G189 V176 N HN N NH
G190 E138 Br
Y188 NH2 N
Butterfly-like shape Etravirine Rilpivirine
(TMC278)
Figure1.2 Pharmacophoresinantiretrovirusagents.
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10 1 OutlookoftheAntiviralDrugEra
PIs
O
H
N
N N N
H
O NH2 OH
O NH
O
CH3SO2 OH H3C CH3
CH3
Saquinavir
NH2
OH
H
O HN N
S
O H O O
H O
O
Darunavir
(TMC-114)
INIs
N HO
N H
O H
N
O N
F O
N N
OH
H
N
O
F O O
O OH
Cl
Raltegravir
Elvitegravir
(MK-0518)
(GS-9137)
CRIs (R5 strains)
F O
H
F HN N N N
N N
F N N
O H
F
F N N
O
Maraviroc Vicriviroc
(SCH-D)
Figure1.2 (Continued)