Non-nucleoside reverse transcriptase inhibitors (NNRTIs) are promising drugs for the treatment of HIV when used in combination with other anti-HIV drugs such as nucleoside reverse transcriptase (RT) inhibitors and protease inhibitors. The first generation of NNRTIs have, however, suffered from the rapid development of resistance. This review discusses the properties of the FDA-approved NNRTI drugs and focuses on the recent efforts being made to produce second generation inhibitors that circumvent this resistance problem.
AhgrenCBackroKBellFWCantrellASClemensMColacinoJMDeeterJBEngelhardtJAHogbergMJaskunasSRJohanssonNGJordanCLKasherJSKinnickMDLindPLopezCMorinJMJrMuesingMANoreenRObergBPagetCJPalkowitzJAParrishCAPrancPRippyMKRydergardCSahlbergCSwansonSTernanskyRJUngeTVasileffRTVrangLWestSJZhangH & ZhouX-X (1995) The PETT series, a new class of potent nonnucleoside inhibitors of human immunodeficiency virus type 1 reverse transcriptase. Antimicrobial Agents and Chemotherapy39: 1329–1335.
2.
AlthausIWGonzalesAJChouJJRomeroDLDeibelMRChouKCKezdyFJResnickLBussoME & SoAG (1993) The quinoline U-78036 is a potent inhibitor of HIV-1 reverse transcriptase. Journal of Biological Chemistry268: 14875–14880.
3.
AlthausIWChouK-CLemayRJFranksKMDeibelMRKezdyFJResnickLBussoMESoAGDowneyKMRomeroDLThomasRCAristoffPATarpleyWG & ReusserF (1996) The benzylthio-pyrimidine U-31, 355, a potent inhibitor of HIV-1 reverse transcriptase. Biochemical Pharmacology51: 743–750.
4.
ArranzEDíazJAIngateSTWitrouwMPannecouqueCBalzariniJDe ClercqE & VegaS (1998) Novel 1,1,3-trioxo-2H, 4H-thieno[3,4-e][1,2,4]thiadiazine derivatives as non-nucleoside reverse transcriptase inhibitors that inhibit human immunodeficiency virus type 1 replication. Journal of Medicinal Chemistry41: 4109–4117.
5.
ArticoM (1996) Non-nucleoside anti-HIV-1 reverse transcriptase inhibitors (NNRTIs): A chemical survey from lead compounds to selected drugs for clinical trials. Il Farmaco51: 305–331.
6.
ArticoMMassaSMaiAMarongiuMEPirasGTramontinoE & La CollaP (1993) 3,4-Dihydro-2-alkoxy-6-benzyl-4-oxopyrimidines (DABOs): A new class of specific inhibitors of human immunodeficiency virus Type 1. Antiviral Chemistry & Chemotherapy4: 361–368.
7.
ArticoMSilvestriRPagnozziEStefancichGMassaSLoiAGPutzoluMCorriasSSpigaMG & La CollaP (1996) 5-H-Pyrrolo[1,2-b][1,2,5]benzothiadiazepines (PBTDs): A novel class of non-nucleoside reverse transcriptase inhibitors. Bioorganic and Medicinal Chemistry Letters4: 837–850.
8.
BabaMYuasaSNiwaTYamamotoMYabuuchiSTakashimaHUbasawaMTanakaHMiyasakaTWalkerRTBalzariniJDe ClercqE & ShigetaS (1993). Effect of human serum on the in vitro anti-HIV-1 activity of 1-[(2Hydroxyethoxy)methyl]-6-(phenylthio)thymine (HEPT) derivatives as related to their lipophilicity and serum protein binding. Biochemical Pharmacology45: 2507–2512.
9.
BaderJPMcMahonJBSchultzRJNarayananVLPierceJBHarrisonWAWeislowOSMidelfortCFStinsonSF & BoydMR (1991) Oxathiin carboxanilide, a potent inhibitor of human immunodeficiency virus reproduction. Proceedings of the National Academy of Sciences, USA88: 6740–6744.
10.
BalzariniJBrouwerWGFelauerEEDe ClercqE & KarlssonA (1995) Activity of various thiocarboxanilide derivatives against wild-type and several mutant human immunodeficiency virus type 1 strains. Antiviral Research27: 219–236.
11.
BarnardJBorkowG & ParniakMA (1997) The thiocarboxanilide nonnucleoside UC781 is a tight-binding inhibitor of HIV-1 reverse transcriptase. Biochemistry36: 7786–7792.
BellFWCantrellASHögbergMJaskunasSRJohanssonNGJordanCLKinnickMDLindPMorinJMJrNoréenRÖbergBPalkowitzJAParrishCAPrancPSahlbergCTernanskyRJVasileffRTVrangLWestSJZhangH & ZhouX-X (1995) Phenethylthiazolethiourea (PETT) compounds, a new class of HIV-1 reverse transcriptase inhibitors. 1. Synthesis and basic structure—activity relationship of PETT analogs. Journal of Medicinal Chemistry38: 4929–4936.
14.
BorkowGBarnardJNguyenTMBelmonteAWainbergMA & ParniakMA (1997) Chemical barriers to human immunodeficiency virus type 1 (HIV-1) infection: Retrovirucidal activity of UC781, a thiocarboxanilide nonnucleoside inhibitor for HIV-1 reverse transcriptase. Journal of Virology71: 3023–3030.
15.
BottaMArticoMMassaSGambacortaAMarongiuMEPaniA & La CollaP (1992) Synthesis, antimicrobial and antiviral activities of isotrimethoprim and some related derivatives. European Journal of Medicinal Chemistry27: 251–257.
16.
BreslinHJKuklaMJLudoviciDWMohrbacherRHoWMirandaMRodgersJDHitchensTKLeoGGauthierDAHoCYScottMKDe ClercqEPauwelsRAndriesKJanssenMAC & JanssenPAJ (1995) Synthesis and anti-HIV-1 activity of 4,5,6,7-tetrahydro-5-methylimidazo[4,5,1-jk][1,4]benzodiazepin-2(1H)-one (TIBO) derivatives. 3. Journal of Medicinal Chemistry38: 771–793.
17.
BuckheitRWJrFliakas-BoltzVRussellJDSnowMPallanschLAYangSSBaderJPKhanTN & ZangerM (1996) A diarylsulphone non-nucleoside reverse transcriptase inhibitor with a unique sensitivity profile to drug resistant virus isolates. Antiviral Chemistry & Chemotherapy7: 243–252.
18.
BuckheitRWJrSnowMJFliakas-BoltzVKinjerskiTLRussellJDPallanschLABrouwerWG & YangSS (1997) Highly potent oxathiin carboxanilide derivatives with efficacy against nonnucleoside reverse transcriptase inhibitor-resistant human immunodeficiency virus isolates. Antimicrobial Agents and Chemotherapy41: 831–837.
19.
CampianiGNacciVFioriniIDe FilippisMPGarofaloAGrecoGNovellinoEAltamuraS & Di RenzoL (1996) Pyrrolobenzothiazepinones and pyrrolobenzoxazepinones: Novel and specific non-nucleoside HIV-1 reverse transcriptase inhibitors with antiviral activity. Journal of Medicinal Chemistry39: 2672–2680.
20.
CantrellASEngelhardtPHögbergMJaskunasSRJohanssonNGJordanCLKangasmetsäJKinnickMDLindPMorinJMJrMuesingMANoreénRÖbergBPrancPSahlbergCTernanskyRJVasileffRTVrangLWestSJ & ZhangH (1996) Phenethylthiazolylthiourea (PETT) compounds as a new class of HIV-1 reverse transcriptase inhibitors. 2. Synthesis and further structure-activity relationship studies of PETT analogs. Journal of Medicinal Chemistry39: 4261–4274.
21.
ChimirriAGrassoSMolicaCMonforteA-MMonfortePZappalaMBrunoGNicoloFWitvrouwMJonckeereHBalzariniJ & De ClercqE (1997) Structural features and anti-human immunodeficiency virus (HIV) activity of the isomers of 1-(2′,6′-difluorophenyl)-1H,3H-thiazolo[3,4-a]benzimidazole, a potent non-nucleoside HIV-1 reverse transcriptase inhibitor. Antiviral Chemistry & Chemotherapy8: 363–370.
22.
CushmanMGolebiewskiMBuckheitRWJrGrahamL & RiceWG (1995) Synthesis and biological evaluation of an alkenyldiarylmethane (ADAM) which acts as a novel non-nucleoside HIV-1 recerse transcriptase inhibitor. Bioorganic & Medicinal Chemistry Letters5: 2713–2716.
23.
CushmanMGolebiewskiWMGrahamLTurpinJARiceWGFliakas-BoltzV & BuckheitRWJr (1996) Synthesis and biological evaluation of certain alkenyldiarylmethanes as anti-HIV-1 agents which act as non-nucleoside reverse transcriptase inhibitors. Journal of Medicinal Chemistry39: 3217–3227.
24.
CushmanMCasimiro-GarciaAHejchmanERuellJAHuangMSchaefferCAWilliamsonKRiceWG & BuckheitRWJr (1998a) New alkenyldiarylmethanes with enhanced potencies as anti-HIV agents which act as non-nucleoside reverse transcriptase inhibitors. Journal of Medicinal Chemistry41: 2076–2089.
25.
CushmanMCasimiro-GarciaAWilliamsonK & RiceWG (1998b) Synthesis of a non-nucleoside reverse transcriptase inhibitor in the alkenyldiarylmethane (ADAM) series with optimized potency and therapeutic index. Bioorganic and Medicinal Chemistry Letters8: 195–198.
26.
CywinCLKlunderJMHoermannMBrickwoodJRDavidEGrobPMSchwartzRPaulettiDBarringerKJShihC-KSorgeCLEricksonDAJosephDP & HattoxSE (1998) Novel nonnucleoside inhibitors of HIV-1 reverse transcriptase. 8. 8-Aryloxymethyl- and 8-arylthiomethyldipyridodiazepinones. Journal of Medicinal Chemistry41: 2972–2984.
27.
DanelKLarsenEPedersenEBVestergaardBF & NielsenC (1996) Synthesis and potent anti-HIV-1 activity of novel 6-benzyluracil analogs of 1-[(2-hydroxyethoxy)methyl]-6-(phenylthio)thymine. Journal of Medicinal Chemistry39: 2427–2431.
28.
DanelKNielsenC & PedersenEB (1997) Anti-HIV active naphtyl analogues of HEPT and DABO. Acta Chemica Scandinavica51: 426–430.
29.
DanelKPedersenEB & NielsenC (1998) Synthesis and anti-HIV-1 activity of novel 2,3-dihydro-7H-thiazolo[3,2-a]pyrimidin-7-ones. Journal of Medicinal Chemistry41: 191–198.
30.
De ClercqE (1998a) The role of non-nucleoside reverse transcriptase inhibitors (NNRTIs) in the therapy of HIV-1 infection. Antiviral Research38: 153–179.
31.
De ClercqE (1998b) New perspectives for the treatment of HIV infections. Collection of Czechoslovak Chemical Communications63: 449–479.
32.
DingJDasKMoereelsHKoymansLAndriesKJanssenPAJHughesSH & ArnoldE (1995) Structure of HIV-1 RT/TIBO R 86183 complex reveals similarity in the binding of diverse nonnucleoside inhibitors. Nature Structural Biology2: 407–415.
33.
DuewekeTJPoppeSMRomeroDLSwaneySMSoAGDowneyKMAlthausIWReusserFBussoMResnickLMayersDLLaneJAristoffPAThomasRC & TarpleyWG (1993) U-90152, a potent inhibitor of human immunodeficiency virus type 1 replication. Antimicrobial Agents and Chemotherapy37: 1127–1131.
34.
FujiwaraTSatoAEl-FarrashMMikiSAbeKIsakaYKodamaMWuYChenBLHaradaHSugimotoHHatanakaM & HinumaY (1998) S-1153 inhibits replication of known drug-resistant strains of human immunodeficiency virus type 1. Antimicrobial Agents and Chemotherapy42: 1340–1345.
35.
FullerRWBokeschHRGustafsonKRMcKeeTCCardellinaJHIIMcMahonJBCraggGMSoejartoDD & BoydMR (1994) HIV-inhibitory coumarins from latex of the tropical rainforest tree Calophyllum teysmannii var. Inophylloide. Bioorganic & Medicinal Chemistry Letters4: 1961–1964.
36.
GalinisDLFullerWTMcKeeTCCardellinaJHIIGulakowskiRJMcMahonJB & BoydMR (1996) Structure—activity modifications of the HIV-1 inhibitors (+)-calanolide A and (–)-calanolide B. Journal of Medicinal Chemistry39: 4507–4510.
37.
GeninMJPoelTJYagiYBilesCAlthausIKeiserBJKoptaLAFriisJMReusserFAdamsWJOlmstedRAVoormanRLThomasRC & RomeroDL (1996) Synthesis and bioactivity of novel bis(heteroaryl)piperazine (BHAP) reverse transcriptase inhibitors: Structure—activity relationship and increased metabolic stability of novel substituted pyridine analogs. Journal of Medicinal Chemistry39: 5267–5275.
38.
GlynnSL & YazdanianM (1998) In vitro blood—brain barrier permeability of nevirapine compared to other HIV antiretroviral agents. Journal of Pharmaceutical Sciences87: 306–310.
39.
GoldmanMENunbergJHO'BrienJAQuinteroJCSchleifWAFreundKFGaulSLSaariWSWaiJSHoffmanJMAndersonPSHupeDJEminiEA & SternAM (1991) Pyridinone derivatives: Specifiic human immunodeficiency virus type 1 reverse transcriptase inhibitors with antiviral activity. Proceedings of the National Academy of Sciences, USA88: 6863–6867.
40.
HanasakiYWatanabeHKatsuuraKTakayamaHShirakawaSYamaguchiKSakaiS-IIjichiKFujiwaraMKonnoKYokotaTShigetaS & BabaM (1995) Thiadiazole derivatives: Highly potent and specific HIV-1 reverse transcriptase inhibitors. Journal of Medicinal Chemistry38: 2038–2040.
41.
HargraveKDProudfootJRGrozingerKGCullenEKapadiaSRPatelURFuchsVUMauldinSCVitousJBehnkeMLKlunderJMPalKSkilesJWMcNeilDWRoseJMChowGCSkoogMTWuJCSchmidtGEngelWWEberleinWGSaboeTDCampbellSJRosenthalAS & AdamsJ (1991) Novel non-nucleoside inhibitors of HIV-1 reverse transcriptase. 1. Tricyclic pyridobenzo- and dipyridodiazepinones. Journal of Medicinal Chemistry34: 2231–2241.
42.
HeinischGHuberEMatuszczakBMaurerA & PrillingerU (1997a) Synthesis of pyridazino[3,4-b][1,5]benzodiazepin-5-ones and their biological evaluation as non-nucleoside HIV reverse transcriptase inhibitors. Archive der Pharmacie330: 29–34.
43.
HeinischGMatuszczakBPachlerS & RakowitzD (1997b) The inhibitory activity of diazinyl-substituted thiourea derivatives on human immunodeficiency virus type 1 reverse transcriptase. Antiviral Chemistry & Chemotherapy8: 443–446.
44.
HirotoHFujihashiTSakataTKajiA & KajiH (1997) Tetrahydronaphtalenelignan compounds as potent anti-HIV type 1 agents. AIDS Research and Human Retroviruses13: 695–705.
45.
HoWKuklaMJBreslinHJLudoviciDWGrousPPDiamondCJMirandaMRodgersJDHoCYDe ClercqEPauwelsRAndriesKJanssenMAC & JanssenPAJ (1995) Synthesis and anti-HIV-1 activity of 4,5,6,7-tetrahydro-5-methylimidazo[4,5,1-jk][1,4]benzodiazepin-2(1H)-one (TIBO) derivatives. 4. Journal of Medicinal Chemistry38: 794–802.
46.
HoffmanJMWaiJSThomasCMLevinRBGoldmanME & O'BrienJA (1992) Synthesis and evaluation of 2-pyridinone derivatives as specific HIV-1 reverse transcriptase inhibitors. 1. Phtalimidoalkyl and -alkylamino analogues. Journal of Medicinal Chemistry35: 3784–3791.
47.
HoffmanJMSmithAMRooneyCSFisherTEWaiJSThomasCMBambergerDLBarnesJLWilliamsTMJonesJHOlsonBDO'BrienJAGoldmanMENunbergJHQuinteroJCSchleifWAEminiEA & AndersonPS (1993) Synthesis and evaluation of 2-pyridinone derivatives as specific reverse transcriptase inhibitors. 4. 3-[2-(Benzoxazol-2-yl)ethyl]-5-ethyl-6-methylpyridin-2(1H)-one and analogues. Journal of Medicinal Chemistry36: 953–966.
48.
HopkinsALRenJEsnoufRMWillcoxBEJonesEYRossCMiyasakaTWalkerRTTanakaHStammersDK & StuartDI (1996). Complexes of HIV-1 reverse transcriptase with inhibitors of the HEPT series reveal conformational changes to the design of potent non-nucleoside inhibitors. Journal of Medicinal Chemistry39: 1589–1600.
49.
IjichiKFujiwaraMNaganoHMatsumotoYHanasakiYIdeTKatsuuraKTakayamaHShirakawaSAimiNShigetaSKonnoKMatsushimaMYokotaT & BabaM (1996) Anti-HIV-1 activity of thiadiazole derivatives: Structure—activity relationship, reverse transcriptase inhibition, and lipophilicity. Antiviral Research31: 87–94.
50.
KashmanYGustafsonKRFullerRWCardellinaJHIIMcMahonJBCurrensMJBuckheitRWJrHughesSHCraggGM & BoydMR (1992) The calanolides, a novel HIV-inhibitory class of coumarin derivatives from the tropical rainforest tree, Calophyllum lanigerum. Journal of Medicinal Chemistry35: 2735–2743.
51.
KellyTAProudfootJRMcNeilDWPatelURDavidEHargraveKDGrobPMCardozoMAgarwalA & AdamsJ (1995) Novel non-nucleoside inhibitors of human immunodeficiency virus type 1 reverse transcriptase. 5. 4-Substituted and 2,4-disubstituted analogs of nevirapine. Journal of Medicinal Chemistry38: 4839–4847.
52.
KellyTAMcNeilDWRoseJMDavidEShihC-K & GrobPM (1997) Novel non-nucleoside inhibitors of human immunodeficiency virus type 1 reverse transcriptase. 6. 2-Indol-3-yl- and 2-azaindol-3-yl-dipyridodiazepinones. Journal of Medicinal Chemistry40: 2430–2433.
53.
KimD-KKimY-WGamJKimGLimJLeeNKimH-T & KimKH (1996) Synthesis and anti-HIV-1 activity of a series of 1-(alkoxymethyl)-5-alkyl-6-(arylselenyl)uracils and -2-thiouracils. Journal of Heterocyclic Chemistry33: 1275–1283.
54.
KleimJ-PBenderRBillhardtU-MMeichsnerCRiessGRîsnerMWinklerI & PaessensA (1993) Activity of a novel quinoxaline derivative against human imunnodeficiency virus type 1 reverse transcriptase and viral replication. Antimicrobial Agents and Chemotherapy37: 1659–1664.
55.
KleimJ-PBenderRKirschRMeichsnerCPaessensARösnerMRüsamen-WaigmannHKaiserRWichersMSchneweisKEWinklerI & ReissG (1995) Preclinical evaluation of HBY 097, a new nonnucleoside reverse transcriptase inhibitor of human immunodeficiency virus type 1 replication. Antimicrobial Agents and Chemotherapy39: 2253–2257.
56.
KlunderJMHargraveKDWestMCullenEPalKBehnkeMKapadiaSRMcNeilDWWuJCChowGC & AdamsJ (1992) Novel non-nucleoside inhibitors of HIV-1 reverse transcriptase. 2. Tricyclic pyridobenzoxazepinones and dibenzoxazepinones. Journal of Medicinal Chemistry35: 1887–1897.
57.
KlunderJMHoermannMCywinCLDavidEBrickwoodJRSchwartzRBarringerKJPaulettiDShihC-KEricksonDASorgeCLJosephDPHattoxSEAdamsJ & GrobPM (1998) Novel nonnucleoside inhibitor of HIV-1 reverse transcriptase. 7. 8-Arylethyldipyridodiazepinones as potenet broad-spectrum inhibitors of wild-type and mutant enzymes. Journal of Medicinal Chemistry41: 2960–2971.
58.
KroegerMBRouzerCATaneyhillLASmithNAHughesSHBoyerPLJanssenPAJMoereelsHKoymansLArnoldEDingJDasKZhangWMichejdaCJ & SmithRHJr (1995) Molecular modelling studies of HIV-1 reverse transcriptase non-nucleoside inhibitors: Total energy of complexation as a predictor of drug placement and activity. Protein Science4: 2203–2222.
59.
KuklaMJBreslinHJPauwelsRFeddeCLMirandaMScottMKSherrillRGRaeymaekersAVan GelderJAndriesKJanssenMACDe ClercqE & JanssenPAJ (1991a) Synthesis and anti-HIV-1 activity of 4,5,6,7-tetrahydro-5-methylimidazo[4,5,1-jk][1,4]benzodiazepin-2(1H)-one (TIBO) derivatives. Journal of Medicinal Chemistry34: 746–751.
60.
KuklaM JBreslinHJDiamondCJGrousPPHoCYMirandaMRodgersJDSherrillRGDe ClercqEPauwelsRAndriesKMoensLJJanssenMAC & JanssenPAJ (1991b) Synthesis and anti-HIV-1 activity of 4,5,6,7-tetrahydro-5-methylimidazo[4,5,1-jk][1,4]benzodiazepin-2(1H)-one (TIBO) derivatives. 2. Journal of Medicinal Chemistry34: 3187–3197.
61.
LarderBAPurifoyDJMPowellKL & DarbyG (1987). Site-specific mutagenesis of AIDS virus reverse transcriptase. Nature327: 716–717.
62.
McMahonJBGulakowskiRJWeislowOSShultzRJNarayananVLClantonDJPedemonteRWassmundtFWBuckheitRWJrDeckerWDWhiteELBaderJP & BoydMR (1993) Diarylsulphones, a new chemical class of nonnucleoside antiviral inhibitors of human immunodeficiency virus type 1 reverse transcriptase. Antimicrobial Agents and Chemotherapy37: 754–760.
63.
MaiAArticoMSbardellaGMassaSLoiAGTramontanoEScanoP & La CollaP (1995) Synthesis and anti-HIV-1 activity of thio analogues of dihydroalkoxybenzyloxopyrimidines. Journal of Medicinal Chemistry38: 3258–3263.
64.
MaiAArticoMSbardellaGQuartaroneSMassaSLoiAGDe MontisAScintuFPutzoluM & La CollaP (1997) Dihydro(alkythio)(naphtylmethyl)oxopyrimidines: Novel non-nucleoside reverse transcriptase inhibitors of the S-DABO series. Journal of Medicinal Chemistry40: 1447–1454.
65.
MaiAArticoMSbardellaGMassaSNovellinoEGrecoGLoiAGTramontanoEMarongiuME & La CollaP (1999). 5-Alkyl-2-(alkylthio)-6-(2,6-dihalophenylmethyl)-3,4-dihydropy-rimidin-4(3H)-ones: Novel potent and selective dihydroalkoxy-benzyl-oxopyrimidine derivatives. Journal of Medicinal Chemistry42: 619–627.
66.
MaoCVigRVenkatachalamTKSudbeckEA & UckunFM (1998) Structure-based design of N-[2-(1-piperidinylethyl)]-N'-[2-(5-bromopyridyl)]-thiourea and N-[2-(1-piperazinylethyl)]-N'-[2-(5-bromopyridyl)]-thiourea as potent non-nucleoside inhibitors of HIV-1 reverse transcriptase. Bioorganic & Medicinal Chemistry Letters8: 2213–2218.
67.
MassaSMaiAArticoMSbardellaGTramontanoELoiAGScanoP & La CollaP (1995) Synthesis and antiviral activity of new 3,4-dihydro-2-alkoxy-6-benzyl-4-oxopyrimidines (DABOs), specific inhibitors of human immunodeficiency virus type 1. Antiviral Chemistry & Chemotherapy6: 1–8.
68.
MerluzziVJHargraveKDLabadiaMGrozingerKSkoogMWuJCShihC-KEcknerKHattoxSAdamsJRosenthalASFaanesREcknerRJKoupRA & SullivanJL (1990) Inhibition of HIV-1 replication by a nonnucleoside reverse transcriptase inhibitor. Science250: 1411–1413.
69.
MertensAZilchHKönigBSchäferWPollTKampeWSeidelHLeiserU & LeinertH (1993) Selective non-nucleoside HIV-1 reverse transcriptase inhibitors. New 2,3-dihydrothiazolo[2,3-a]isoindol-5(9bH)-ones and related compounds with anti-HIV-1 activity. Journal of Medicinal Chemistry36: 2526–2536.
70.
MillerVde BethuneM-PKoberAStürmerMHertogsKPauwelsRStoffelsP & StaszewskiS (1998) Patterns of resistance and cross-resistance to human immunodeficiency virus type 1 reverse transcriptase inhibitors in patients treated with the nonnucleoside reverse transcriptase inhibitor loviride. Antimicrobial Agents and Chemotherapy42: 3123–3129.
71.
MiyasakaTTanakaHBabaMHayakawaHWalkerRTBalzariniJ & De ClercqE (1989) A novel lead for specific anti-HIV-1 agents: 1-[(2hydroxyethoxy)methyl]-6-(phenylthio)thymine. Journal of Medicinal Chemistry32: 2507–2509.
72.
NeamatiNMazumderAZhaoHSunderSBurkeTRJrSchultzRJ & PommierY (1997) Diarylsulfones, a novel class of human immunodeficiency virus type 1 integrase inhibitors. Antimicrobial Agents and Chemotherapy41: 385–393.
73.
NugentARSchlachterSTMurphyMJCleekGJPoelTJWishkaDGGraberDRYagiYKeiserBJOlmstedRAKoptaLASwaneySMPoppeSMMorrisJTarpleyWG & ThomasRC (1998) Pyrimidine thioethers: A novel class of HIV-1 reverse transcriptase inhibitors with activity against BHAP-resistant HIV. Journal of Medicinal Chemistry41: 3793–3803.
74.
NunbergJHSchleifWABootsEJO'BrienJAQuinteroJCHoffmanJMEminiEA & GoldmanME (1991) Viral resistance to human immunodeficiency virus type 1-specific pyridinone reverse transcriptase inhibitors. Journal of Virology65: 4887–4892.
75.
PauwelsRAndriesKDesmyterJScholsDKuklaMJBreslinHJRaeymaeckersAVan GelderJWoestenborghsRHeykantsJSchellekensKJanssenACMDe ClercqE & JanssenPAJ (1990) Potent and selective inhibition of HIV-1 replication in vitro by a novel series of TIBO derivatives. Nature343: 470–474.
76.
PauwelsRAndriesKDebyserZVan DaelePScholsDStoffelsPDe VreeseKWoestenborghsRVandammeA-MJanssenCGMAnneJCauwenberghGDesmyterJHeykantsJJanssenMACDe ClercqE & JanssenPAJ (1993) Potent and highly selective human immunodeficiency virus type 1 (HIV-1) inhibition by a series of α-anilinophenylacetamide derivatives targeted at HIV-1 reverse transcriptase. Proceedings of the National Academy of Sciences, USA90: 1711–1715.
77.
PauwelsRAndriesKDebyserZKuklaMJScholsDBreslinHJWoestenborghsRDesmyterJJanssenMACDe ClercqE & JanssenPAJ (1994) New tetrahydroimidazo[4,5,1-jk][1,4]-benzodiazepin-2(1H)-one and thione derivates are potent inhibitors of human immunodeficiency virus type 1 replication and are synergistic with 2′,3′-dideoxynucleoside analogs. Antimicrobial Agents and Chemotherapy38: 2863–2870.
78.
PontikisRBenhidaRAubertinA-MGriersonDS & MonneretC (1997) Synthesis and anti-HIV activity of novel N-1 side chain-modified analogs of 1-[(2-hydroxyethoxy)methyl]-6-(phenylthio)thymine (HEPT). Journal of Medicinal Chemistry40: 1845–1854.
79.
ProudfootJRHargraveKDKapadiaSRPatelURGrozingerKGMcNeilDWCullenECardozoMTongLKellyTARoseJDavidEMauldinSCFuchsVUVitousJHoermannMKlunderJMRaghavenPSkilesJWMuiPRichmanDDSullivanJLShihC-KGrobPM & AdamsJ (1995a) Novel non-nucleoside inhibitors of human immunodeficiency virus type 1 (HIV-1) reverse transcriptase. 4. 2-Substituted dipyridodiazepinones as potent inhibitors of both wild-type and cysteine-181 HIV-1 reverse transcriptase enzymes. Journal of Medicinal Chemistry38: 4830–4838.
80.
ProudfootJRPatelURKapadiaSR & HargraveKD (1995b) Novel non-nucleoside inhibitors of HIV-1 reverse transcriptase. 3. Dipyrido[2,3-b:2′,3′-e]diazepinones. Journal of Medicinal Chemistry38: 1406–1410.
81.
RenJEsnoufRHopkinsARossCJonesYStammersD & StuartD (1995) The structure of HIV-1 reverse transcriptase complexed with 9-chloro-TIBO: Lessons for inhibitor design. Structure3: 915–926.
82.
RomeroDLBussoMTanC-KReusserFPalmerJRPoppeSMAristoffPADowneyKMSoAGResnickL & TarpleyWG (1991) Nonnucleoside reverse transcriptase inhibitors that potently and specifically block human immunodeficiency virus type 1 replication. Proceedings of the National Academy of Sciences, USA88: 8806–8810.
83.
RomeroDLMorgeRABilesCBerrios-PenaNMayPDPalmerJRJohnsonPDSmithHWBussoMTanC-KVoormanRLReusserFAlthausIWDowneyKMSoAGResnickLTarpleyWG & AristoffPA (1994) Discovery, synthesis, and bioactivity of bis(heteroaryl)piperazines. 1. A novel class of non-nucleoside HIV-1 reverse transcriptase inhibitors. Journal of Medicinal Chemistry37: 999–1014.
84.
RomeroDLOlmstedRAPoelTJMorgeRABilesCKeiserBJKoptaLAFriisJMHosleyJDStefanskiKJWishkaDGEvansDBMorrisJStehleRGSharmaSKYagiYVoormanRLAdamsWJTarpleyWG & ThomasRC (1996) Targeting delavirdine/atevirdine resistant HIV-1: Identification of (alkylamino)piperidine-containing bis(heteroaryl)piperazines as broad spectrum HIV-1 reverse transcriptase inhibitors. Journal of Medicinal Chemistry39: 3769–3789.
85.
RothTMorningstarMLBoyerPLHughesSHBuckheitRWJr & MichejdaCJ (1997) Synthesis and biological activity of novel nonnucleoside inhibitors of HIV-1 reverse transcriptase. 2-Aryl-substituted benzimidazoles. Journal of Medicinal Chemistry40: 4199–4207.
86.
SaariWSWaiJSFisherTEThomasCMHoffmanJMRooneyCSSmithAMJonesJHBambergerDLGoldmanMEO'BrienJANunbergJHQuinteroJCSchleifWAEminiEA & AndersonPS (1992) Synthesis and evaluation of 2-pyridinone derivatives as specific HIV-1-reverse transcriptase inhibitors. 2. Analogs of 3-aminopyridin-2(1H)-one. Journal of Medicinal Chemistry35: 3792–3802.
87.
SahlbergCNoreenREngelhardtPHögbergMKangasmetsäJVrangL & ZhangH (1998) Synthesis and anti-HIV activities of urea-PETT analogs belonging to a new class of potent non-nucleoside HIV-1 reverse transcriptase inhibitors. Bioorganic and Medicinal Chemistry Letters8: 1511–1516.
88.
SilvestriRArticoMMassaSStefancichGCongedduEPutzoluM & La CollaP (1997). Sulfone derivatives with anti-HIV activity. Il Farmaco52: 323–329.
89.
SudbeckEAMaoCVigRVenkatachalamTKTuel-AhlgrenL & UckunFM (1998) Structure-based design of novel dihydroalkoxy-benzyloxopyrimidine derivatives as potent nonnucleoside inhibitors of the human immunodeficiency virus reverse transcriptase. Antimicrobial Agents and Chemotherapy42: 3225–3233.
90.
TanakaHBabaMSaitoSMiyasakaTTakashimaHSekiyaKUbasawaMNittaIWalkerRTNakashimaH & De ClercqE (1991) Specific anti-HIV-1 ‘acyclonucleosides’ which cannot be phosphorylated: Synthesis of some deoxy analogues of 1-[(2-hydroxyethoxy)methyl]-6-(phenylthio)thymine. Journal of Medicinal Chemistry34: 1508–1511.
91.
TanakaHTakashimaHUbasawaMSekiyaKNittaIBabaMShigetaSWalkerRTDe ClercqE & MiyasakaT (1992a) Structure—activity relationships of 1-[(2-hydroxyethoxy)methyl]-6-(phenylthio)thymine analogues: Effect of substitutions at the C-6 phenyl ring and at the C-5 position on anti-HIV-1 activity. Journal of Medicinal Chemistry35: 337–345.
92.
TanakaHTakashimaHUbasawaHSekiyaKNittaIBabaMShigetaSWalkerRTDe ClercqE & MiyasakaT (1992b) Synthesis and antiviral activity of deoxy analogs of 1-[(2-hydroxyethoxy)methyl]-6-(phenylthio)thymine (HEPT) as potent and selective anti-HIV-1 agents. Journal of Medicinal Chemistry35: 4713–4719.
93.
TanakaHTakashimaHUbasawaMSekiyaKInouyeNBabaMShigetaSWalkerRTDe ClercqE & MiyasakaT (1995) Synthesis and antiviral activity of 6-benzyl analogs of 1-[(2-hydroxyethoxy)methyl]-6-(phenylthio)thymine (HEPT) as potent and selective anti-HIV-1 agents. Journal of Medicinal Chemistry38: 2860–2865.
94.
TantilloCDingJJacobo-MolinaANanniRGBoyerPLHughesSHPauwelsRAndriesKJanssenPAJ & ArnoldE (1994) Locations of anti-AIDS drug binding sites and resistance mutations in the three-dimensional structure of HIV-1 reverse transcriptase. Journal of Molecular Biology243: 369–387.
95.
TuckerTJLummaWC & CulbersonJC (1996) Development of nonnucleoside HIV reverse transcriptase inhibitors. Methods in Enzymology275: 440–472.
96.
VelázquezSAlvarezRPerezCGagoFDe ClercqEBalzariniJ & CamarasaM-J (1998) Regiospecific synthesis and anti-human immunodeficiency virus activity of novel 5-substituted N-alkylcar-bamoyl and N,N-dialkyl carbamoyl 1,2,3-triazole-TSAO analogues. Antiviral Chemistry & Chemotherapy9: 481–489.
97.
VigRMaoCVenkatachalamTKTuel-AhlgrenLSudbeckEA & UckunFM (1998) Rational design and synthesis of phenethyl-5-bromopyridyl thiourea derivatives as potent non-nucleoside inhibitors of HIV reverse transcriptase. Bioorganic & Medicinal Chemistry6: 1789–1797.
98.
WaiJSWilliamsTMBambergerDLFisherTEHoffmanJMHudcoskyRJMacToughSCRooneyCSSaariWSThomasCMGoldmanMEO'BrienJAEminiEANunbergJHQuinteroJCSchleifWA & AndersonPS (1993) Synthesis and evaluation of 2-pyridinone derivatives as specific HIV-1 reverse transcriptase Inhibitors. 3. Pyridyl and phenyl analogs of 3-aminopyridin-2(1H)-one. Journal of Medicinal Chemistry36: 249–255.
99.
WilliamsTMCiccaroneTMMacToughSCRooneyCSBalaniSKCondraJHEminiEAGoldmanMEGreenleeWJKauffmanLRO'BrienJASardanaVVSchleifWATheoharidesAD & AndersonPS (1993) 5-Chloro-3-(phenylsulfonyl)indole-2-carboxamide: A novel, non-nucleoside inhibitor of HIV-1 reverse transcriptase. Journal of Medicinal Chemistry36: 1291–1294.
100.
WishkaDGGraberDRKoptaLAOlmstedRAFriisJMHosleyJDAdamsWJSeestEPCastleTMDolakLAKeiserBJYagiYJeganathanASchlachterSTMurphyMJCleekGJNugentRAPoppeSMSwaneySMHanFWattWWhiteWLPoelT-JThomasRCVoormanRLStefanskiKJStehleRGTarpleyWG & MorrisJ (1998a) (–)-6-Chloro-2-[(1-furo[2,3-c]pyridin-5-yl-ethyl)thio]-4-pyrimidinamine, PNU-142721, a new broad spectrum HIV-1 non-nucleoside reverse transcriptase inhibitor. Journal of Medicinal Chemistry41: 1357–1360.
101.
WishkaDGGraberDRSeestEPDolakADHanFWattW & MorrisJ (1998b) Stereoselective synthesis of furo[2,3-c]pyridine pyrimidine thioethers, a new class of potent HIV-1 non-nucleoside reverse transcriptase inhibitors. Journal of Organic Chemistry63: 7851–7859.
102.
WitvrouwMArranzMEPannecouqueCDeclerqRJonckheereHSchmitJ-CVandammeA-MDiazJAIngateSTDesmyterJEsnoufRVan MeerveltLVegaSBalzariniJ & De ClercqE (1998) 1,1,3-Trioxo-2H,4H-thieno[3,4-e][1,2,4]thiadiazine (TTD) derivatives: A new class of nonnucleoside human immunodeficiency virus type 1 (HIV-1) reverse transcriptase inhibitors with anti-HIV-1 activity. Antimicrobial Agents and Chemotherapy42: 618–623.
103.
YoungSDBritcherSFTranLOPayneLSLummaWCLyleTAHuffJRAndersonPSOlsenDBCarrollSSPettiboneDJO'BrienJABallRGBalaniSKLinJHChenI-WSchleifWASardanaVVLongWJByrnesVW & EminiEA (1995a) L-743,726 (DMP-266): A novel, highly potent nonnucleoside inhibitor of the human immunodeficiency virus type 1 reverse transcriptase. Antimicrobial Agents and Chemotherapy39: 2602–2605.
ZembowerDELiaoSFlavinMTXuZ-QStupTLBuckheitRWJrKhilevichAMarAA & SheinkmanAK (1997) Structural analogues of the calanolide anti-HIV agents. Modification of the trans-10,11-dimethyldihydropyran-12-ol ring (ring C). Journal of Medicinal Chemistry40: 1005–1017.