The role of non-nucleoside reverse transcriptase inhibitors (NNRTIs) in the therapy of HIV-1 infection1Presented at the Eleventh International Conference on Antiviral Research, San Diego, CA, 5–10 April 1998.1

Antiviral Research - Tập 38 Số 3 - Trang 153-179 - 1998
Erik De Clercq1
1Rega Institute for Medical Research, Katholieke Universiteit Leuven, Minderbroedersstraat 10, B‐3000 Leuven, Belgium.

Tóm tắt

Từ khóa


Tài liệu tham khảo

Ahrgren, 1995, The PETT series, a new class of potent nonnucleoside inhibitors of human immunodeficiency virus type 1 reverse transcriptase, Antimicrob. Agents Chemother., 39, 1329, 10.1128/AAC.39.6.1329

Althaus, 1996, The benzylthio-pyrimidine U-31,355, a potent inhibitor of HIV-1 reverse transcriptase, Biochem. Pharmacol., 51, 743, 10.1016/0006-2952(95)02390-9

Antonucci, 1995, Characterization of the antiviral activity of highly substituted pyrroles: a novel class of non-nucleoside HIV-1 reverse transcriptase inhibitor, Antiviral Chem. Chemother., 6, 98, 10.1177/095632029500600204

Artico, 1993, 3,4-Dihydro-2-alkoxy-6-benzyl-4-oxopyrimidines (DABOs): a new class of specific inhibitors of human immunodeficiency virus type 1, Antiviral Chem. Chemother., 4, 361, 10.1177/095632029300400608

Baba, 1989, Highly specific inhibition of human immunodeficiency virus type 1 by a novel 6-substituted acyclouridine derivative, Biochem. Biophys. Res. Commun., 165, 1375, 10.1016/0006-291X(89)92756-3

Baba, 1991, Potent and selective inhibition of human immunodeficiency virus type 1 (HIV-1) by 5-ethyl-6-phenylthiouracil derivatives through their interaction with the HIV-1 reverse transcriptase, Proc. Natl. Acad. Sci. USA, 88, 2356, 10.1073/pnas.88.6.2356

Baba, 1991, Highly potent and selective inhibition of human immunodeficiency virus type 1 by a novel series of 6-substituted acyclouridine derivatives, Mol. Pharmacol., 39, 805

Baba, 1994, Preclinical evaluation of MKC-442, a highly potent and specific inhibitor of human immunodeficiency virus type 1 in vitro, Antimicrob. Agents Chemother., 38, 688, 10.1128/AAC.38.4.688

Balzarini, 1997, The thiocarboxanilides UC-10 and UC-781 have an additive inhibitory effect against human immunodeficiency virus type 1 reverse transcriptase and replication in cell culture when combined with other antiretroviral drugs, Antiviral Chem. Chemother., 8, 197, 10.1177/095632029700800303

Balzarini, 1992, 2′,5′-Bis-O-(tert.-butyldimethylsilyl)-3′-spiro-5′′(4′′amino-1′′,2′′oxathiole-2′′,2′′-dioxide)pyrimidine (TSAO) nucleoside analogues: novel highly selective inhibitors of human immunodeficiency virus type 1 that are targeted at the viral reverse transcriptase, Proc. Natl. Acad. Sci. USA, 89, 4392, 10.1073/pnas.89.10.4392

Balzarini, 1992, [2′,5′-Bis-O-(tert-butyldimethylsilyl)]-3′-spiro-5′′-[4′′-amino-1′′,2′′-oxathiole-2′′,2′′-dioxide) (TSAO) derivatives of purine and pyrimidine nucleosides as potent and selective inhibitors of human immunodeficiency virus type 1, Antimicrob. Agents Chemother., 36, 1073, 10.1128/AAC.36.5.1073

Balzarini, 1992, Kinetics of inhibition of human immunodeficiency virus type 1 (HIV-1) reverse transcriptase by the novel HIV-1-specific nucleoside analogue [2′,5′-bis-O-(tert-butyldimethylsilyl)-β-d-ribofuranosyl]-3′-spiro-5′′-(4′′-amino-1′′,2′′-oxathiole-2′′,2′′-di-oxide)thymine (TSAO-T), J. Biol. Chem., 267, 11831, 10.1016/S0021-9258(19)49774-3

Balzarini, 1993, Knocking-out concentrations of HIV-1-specific inhibitors completely suppress HIV-1 infection and prevent the emergence of drug-resistant virus, Virology, 196, 576, 10.1006/viro.1993.1513

Balzarini, 1994, Resistance pattern of human immunodeficiency virus type 1 reverse transcriptase to quinoxaline S-2720, J. Virol., 68, 7986, 10.1128/JVI.68.12.7986-7992.1994

Balzarini, 1995, Activity of various thiocarboxanilide derivatives against wild-type and several mutant human immunodeficiency virus type 1 strains, Antiviral Res., 27, 219, 10.1016/0166-3542(95)00006-8

Balzarini, 1995, Differential activities of 1-[(2-hydroxyethoxy)methyl]-6-(phenylthio)thymine derivatives against different human immunodeficiency virus type 1 mutant strains, Antimicrob. Agents Chemother., 39, 998, 10.1128/AAC.39.4.998

Balzarini, 1995, Suppression of the breakthrough of human immunodeficiency virus type 1 (HIV-1) in cell culture by thiocarboxanilide derivatives when used individually or in combination with other HIV-1-specific inhibitors (i.e. TSAO derivatives), Proc. Natl. Acad. Sci. USA, 92, 5470, 10.1073/pnas.92.12.5470

Balzarini, 1996, Marked inhibitory activity of non-nucleoside reverse transcriptase inhibitors against human immunodeficiency virus type 1 when combined with (-)2′,3′-dideoxy-3′-thiacytidine, Mol. Pharmacol., 49, 882

Balzarini, 1996, Highly favorable antiviral activity and resistance profile of the novel thiocarboxanilide pentenyloxy ether derivatives UC-781 and UC-82 as inhibitors of human immunodeficiency virus type 1 replication, Mol. Pharmacol., 50, 394

Balzarini, 1996, Concomitant combination therapy for HIV infection preferable over sequential therapy with 3TC and non-nucleoside reverse transcriptase inhibitors, Proc. Natl. Acad. Sci. USA, 93, 13152, 10.1073/pnas.93.23.13152

Balzarini, 1997, Zidovudine-resistant human immunodeficiency virus type 1 strains subcultured in the presence of both lamivudine and quinoxaline HBY 097 retain marked sensitivity to HBY 097 but not to lamivudine, J. Infect. Dis., 176, 1392, 10.1086/517329

Balzarini, 1998, A novel mutation (F227L) arises in the reverse transcriptase of human immunodeficiency virus type 1 on dose-escalating treatment of HIV type 1-infected cell cultures with the nonnucleoside reverse transcriptase inhibitor thiocarboxanilide UC-781, AIDS Res. Hum. Retroviruses, 14, 255, 10.1089/aid.1998.14.255

Balzarini, 1998, Retention of marked sensitivity to (S)-4-isopropoxycarbonyl-6-methoxy-3-(methylthiomethyl)-3,4-dihydroquinoxaline-2(1H)-thione (HBY 097) by an azidothymidine (AZT)-resistant human immunodeficiency virus type 1 (HIV-1) strain subcultured in the combined presence of quinoxaline HBY 097 and 2′,3′-dideoxy-3′-thiacytidine (lamivudine), Biochem. Pharmacol., 55, 617, 10.1016/S0006-2952(97)00506-6

Barth, 1996, Pyridazino[3,4-b][1,5]benzoxazepin-5(6H)-ones: synthesis and biological evaluation, Antiviral Chem. Chemother., 7, 300, 10.1177/095632029600700603

Bellarosa, 1996, New arylpyrido-diazepine and -thiodiazepine derivatives are potent and highly selective HIV-1 inhibitors targeted at the reverse transcriptase, Antiviral Res., 30, 109, 10.1016/0166-3542(95)00906-X

Boyer, 1994, Subunit specificity of mutations that confer resistance to nonnucleoside inhibitors in human immunodeficiency virus type 1 reverse transcriptase, Antimicrob. Agents Chemother., 38, 1909, 10.1128/AAC.38.9.1909

Boyer, 1998, A mutation at position 190 of human immunodeficiency virus type 1 reverse transcriptase interacts with mutations at positions 74 and 75 via the template primer, Antimicrob. Agents Chemother., 42, 447, 10.1128/AAC.42.2.447

Brennan, 1995, The inhibition of human immunodeficiency virus type 1 in vitro by a non-nucleoside reverse transcriptase inhibitor MKC-442, alone and in combination with other anti-HIV compounds, Antiviral Res., 26, 173, 10.1016/0166-3542(94)00074-I

Buckheit, 1993, Thiazolobenzimidazole: biological and biochemical anti-retroviral activity of a new nonnucleoside reverse transcriptase inhibitor, Antiviral Res., 21, 247, 10.1016/0166-3542(93)90031-D

Buckheit, 1994, Biological and biochemical anti-HIV activity of the benzothiadiazine class of nonnucleoside reverse transcriptase inhibitors, Antiviral Res., 25, 43, 10.1016/0166-3542(94)90092-2

Buckheit, 1994, Cell-based and biochemical analysis of the anti-HIV activity of combinations of 3′-azido-3′-deoxythymidine and analogues of TIBO, Antiviral Chem. Chemother., 5, 35, 10.1177/095632029400500105

Buckheit, 1995, Resistance to 1-[(2-hydroxyethoxy)methyl]-6-(phenylthio)thymine derivatives is generated by mutations at multiple sites in the HIV-1 reverse transcriptase, Virology, 210, 186, 10.1006/viro.1995.1330

Buckheit, 1997, Highly potent oxathiin carboxanilide derivatives with efficacy against nonnucleoside reverse transcriptase inhibitor-resistant human immunodeficiency virus isolates, Antimicrob. Agents Chemother., 41, 831, 10.1128/AAC.41.4.831

Byrnes, 1994, Susceptibilities of human immunodeficiency virus type 1 enzyme and viral variants expressing multiple resistance-engendering amino acid substitutions to reverse transcriptase inhibitors, Antimicrob. Agents Chemother., 38, 1404, 10.1128/AAC.38.6.1404

1997, Randomised trial of addition of lamivudine or lamivudine plus loviride to zidovudine-containing regimens for patients with HIV-1 infection: the CAESAR trial, Lancet, 349, 1413, 10.1016/S0140-6736(97)04441-3

Campiani, 1996, Pyrrolobenzothiazepinones and pyrrolobenzoxazepinones: novel and specific non-nucleoside HIV-1 reverse transcriptase inhibitors with antiviral activity, J. Med. Chem., 39, 2672, 10.1021/jm950702c

Cao, 1995, Virologic and immunologic characterization of long-term survivors of human immunodeficiency virus type 1 infection, New Engl. J. Med., 332, 201, 10.1056/NEJM199501263320401

Carr, 1996, A controlled trial of nevirapine plus zidovudine versus zidovudine alone in p24 antigenaemic HIV-infected patients, AIDS, 10, 635, 10.1097/00002030-199606000-00009

Chimirri, 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 Chem. Chemother., 8, 363, 10.1177/095632029700800409

Chong, 1994, Bisheteroarylpiperazine reverse transcriptase inhibitor in combination with 3′-azido-3′-deoxythymidine or 2′,3′-dideoxycytidine synergistically inhibits human immunodeficiency virus type 1 replication in vitro, Antimicrob. Agents Chemother., 38, 288, 10.1128/AAC.38.2.288

Craib, 1997, Serum levels of human immunodeficiency virus type 1 (HIV-1) RNA after seroconversion: a predictor of long-term mortality in HIV infection, J. Infect. Dis., 176, 798, 10.1086/517305

D'Aquila, 1996, Nevirapine, zidovudine, and didanosine compared with zidovudine and didanosine in patients with HIV-1 infection. A randomized, double-blind, placebo-controlled trial, Ann. Intern. Med., 124, 1019, 10.7326/0003-4819-124-12-199606150-00001

Davey, 1993, Plasma viremia as a sensitive indicator of the antiretroviral activity of L-697,661, Proc. Natl. Acad. Sci. USA, 90, 5608, 10.1073/pnas.90.12.5608

Davey, 1996, Randomized, controlled phase I/II trial of combination therapy with delavirdine (U-90152S) and conventional nucleosides in human immunodeficiency virus type 1-infected patients, Antimicrob. Agents Chemother., 40, 1657, 10.1128/AAC.40.7.1657

Debyser, 1991, An antiviral target on reverse transcriptase of human immunodeficiency virus type 1 revealed by tetrahydroimidazo-[4,5,1-jk][1,4]benzodiazepin-2(1H)-one and -thione derivatives, Proc. Natl. Acad. Sci. USA, 88, 1451, 10.1073/pnas.88.4.1451

Debyser, 1992, Common features in the interaction of tetrahydroimidazo[4,5,1-jk][1,4]benzodiazepin-2(1H)-one and -thione and 1-[(2-hydroxyethoxy)methyl]-6-(phenylthio)thymine derivatives with the human immunodeficiency virus type 1 reverse transcriptase, Mol. Pharmacol., 41, 963

De Clercq, 1995, Antiviral therapy for human immunodeficiency virus infections, Clin. Microbiol. Rev., 8, 200, 10.1128/CMR.8.2.200

De Clercq, 1996, Non-nucleoside reverse transcriptase inhibitors (NNRTIs) for the treatment of human immunodeficiency virus type 1 (HIV-1) infections: strategies to overcome drug resistance development, Med. Res. Rev., 16, 125, 10.1002/(SICI)1098-1128(199603)16:2<125::AID-MED1>3.0.CO;2-2

De Clercq, 1996, What can be expected from non-nucleoside reverse transcriptase inhibitors (NNRTIs) in the treatment of human immunodeficiency virus type 1 (HIV-1) infections?, Rev. Med. Virol., 6, 97, 10.1002/(SICI)1099-1654(199606)6:2<97::AID-RMV168>3.0.CO;2-4

De Clercq, 1997, In search of a selective antiviral chemotherapy, Clin. Microbiol. Rev., 10, 674, 10.1128/CMR.10.4.674

De Jong, 1997, High-dose nevirapine in previously untreated human immunodeficiency virus type 1-infected persons does not result in sustained suppression of viral replication, J. Infect. Dis., 175, 966, 10.1086/514002

De Lucca, 1992, Synthesis and anti-HIV activity of pyrrolo-[1,2-d]-(1,4)-benzodiazepin-6-ones, Bioorg. Med. Chem. Lett., 2, 1639, 10.1016/S0960-894X(00)80447-3

De Wit, 1992, Pharmacokinetics of R 82913 in AIDS patients: a phase I dose-finding study of oral administration compared with intravenous infusion, Antimicrob. Agents Chemother., 36, 2661, 10.1128/AAC.36.12.2661

Ding, 1995, Structure of HIV-1 reverse transcriptase in a complex with the non-nucleoside inhibitor α-APA R 95845 at 2.8 Å resolution, Structure, 3, 365, 10.1016/S0969-2126(01)00168-X

Ding, 1995, Structure of HIV-1 RT/TIBO R86183 complex reveals similarity in the binding of diverse nonnucleoside inhibitors, Struct. Biol., 2, 407, 10.1038/nsb0595-407

Di Santo, 1998, 1,2,5-Benzothiadiazepine and pyrrolo[2,1-d][1,2,5]benzothiadiazepine derivatives with specific anti-human immunodeficiency virus type 1 activity, Antiviral Chem. Chemother., 9, 127, 10.1177/095632029800900204

Dollé, 1995, A new series of pyridinone derivatives as potent non-nucleoside human immunodeficiency virus type 1 specific reverse transcriptase inhibitors, J. Med. Chem., 38, 4679, 10.1021/jm00023a007

Dueweke, 1992, The binding of a novel bisheteroarylpiperazine mediates inhibition of human immunodeficiency virus type 1 reverse transcriptase, J. Biol. Chem., 267, 27, 10.1016/S0021-9258(18)48451-7

Dueweke, 1993, U-90152, a potent inhibitor of human immunodeficiency virus type 1 replication, Antimicrob. Agents Chemother., 37, 1127, 10.1128/AAC.37.5.1127

Dueweke, 1993, A mutation in reverse transcriptase of bis(heteroaryl)piperazine-resistant human immunodeficiency virus type 1 that confers increased sensitivity to other nonnucleoside inhibitors, Proc. Natl. Acad. Sci. USA, 90, 4713, 10.1073/pnas.90.10.4713

Esnouf, 1997, An extensively modified version of MolScript that includes greatly enhanced coloring capabilities, J. Mol. Graphics, 15, 132, 10.1016/S1093-3263(97)00021-1

Esnouf, 1995, Mechanism of inhibition of HIV-1 reverse transcriptase by non-nucleoside inhibitors, Struct. Biol., 2, 303, 10.1038/nsb0495-303

Esnouf, 1997, Unique features in the structure of the complex between HIV-1 reverse transcriptase and the bis(heteroaryl)piperazine (BHAP) U-90152 explain resistance mutations for this nonnucleoside inhibitor, Proc. Natl. Acad. Sci. USA, 94, 3984, 10.1073/pnas.94.8.3984

Esnouf, 1997, Models which explain the inhibition of reverse transcriptase by HIV-1-specific (thio)carboxanilide derivatives, Biochem. Biophys. Res. Commun., 234, 458, 10.1006/bbrc.1997.6552

Finzi, 1997, Identification of a reservoir for HIV-1 in patients on highly active antiretroviral therapy, Science, 279, 1295, 10.1126/science.278.5341.1295

Goldman, 1991, Pyridinone derivatives: specific human immunodeficiency virus type 1 reverse transcriptase inhibitors with antiviral activity, Proc. Natl. Acad. Sci. USA, 88, 6863, 10.1073/pnas.88.15.6863

Goldman, 1992, L-696,229 specifically inhibits human immunodeficiency virus type 1 reverse transcriptase and possesses antiviral activity in vitro, Antimicrob. Agents Chemother., 36, 1019, 10.1128/AAC.36.5.1019

Grob, 1997, Prophylaxis against HIV-1 infection in chimpanzees by nevirapine, a nonnucleoside inhibitor of reverse transcriptase, Nat. Med., 3, 665, 10.1038/nm0697-665

Havlir, 1996, Viral dynamics of HIV: implications for drug development and therapeutic strategies, Ann. Intern. Med., 124, 984, 10.7326/0003-4819-124-11-199606010-00006

Havlir, 1995, High-dose nevirapine: safety, pharmacokinetics, and antiviral effect in patients with human immunodeficiency virus infection, J. Infect. Dis., 171, 537, 10.1093/infdis/171.3.537

Havlir, 1995, A pilot study to evaluate the development of resistance to nevirapine in asymptomatic human immunodeficiency virus-infected patients with CD4 cell counts of >500/mm3: AIDS clinical trials group protocol 208, J. Infect. Dis., 172, 1379, 10.1093/infdis/172.5.1379

Ho, 1995, Rapid turnover of plasma virions and CD4 lymphocytes in HIV-1 infection, Nature, 373, 123, 10.1038/373123a0

Ijichi, 1995, Potent and specific inhibition of human immunodeficiency virus type 1 replication by 4-(2,6-dichlorophenyl)-1,2,5-thiadiazol-3-Y1 N,N-dialkylcarbamate derivatives, Antimicrob. Agents Chemother., 39, 2337, 10.1128/AAC.39.10.2337

Ijichi, 1996, Anti-HIV-1 activity of thiadiazole derivatives: a structure–activity relationship, reverse transcriptase inhibition, and lipophilicity, Antiviral Res., 31, 87, 10.1016/0166-3542(96)00950-3

Ito, 1991, Synergistic inhibition of human immunodeficiency virus type 1 (HIV-1) replication in vitro by 1-[(2-hydroxyethoxy)methyl]-6-phenylthiothymine (HEPT) and recombinant alpha interferon, Antiviral Res., 15, 323, 10.1016/0166-3542(91)90013-H

Jonckheere, 1994, Resistance of HIV-1 reverse transcriptase against [2′,5′-bis-O-(tert-butyldimethylsilyl)-3′-spiro-5′′-(4′′-amino-1′′,2′′-oxathiole-2′′,2′′-dioxide)] (TSAO) derivatives is determined by the mutation Glu138→Lys on the p51 subunit, J. Biol. Chem., 269, 25255, 10.1016/S0021-9258(18)47240-7

Jourdan, 1997, Design, synthesis and antiviral activity of new pyridinone derivatives, Antiviral Chem. Chemother., 8, 161, 10.1177/095632029700800210

Kashman, 1992, The calanolides, a novel HIV-inhibitory class of coumarin derivatives from the tropical rainforest tree, Calophyllum lanigerum, J. Med. Chem., 35, 2735, 10.1021/jm00093a004

Kelly, 1997, Novel non-nucleoside inhibitors of human immunodeficiency virus type 1 reverse transcriptase. 6. 2-Indol-3-yl- and 2-azaindol-3-yl-dipyridodiazepinones, J. Med. Chem., 40, 2430, 10.1021/jm960837y

Kim, 1997, Synthesis and anti-HIV-1 activity of a series of 1-alkoxy-5-alkyl-6-(arylthio)uracils, J. Med. Chem., 40, 2363, 10.1021/jm9607921

Kleim, 1993, Activity of a novel quinoxaline derivative against human immunodeficiency virus type 1 reverse transcriptase and viral replication, Antimicrob. Agents Chemother., 37, 1659, 10.1128/AAC.37.8.1659

Kleim, 1994, Mutational analysis of residue 190 of human immunodeficiency virus type 1 reverse transcriptase, Virology, 200, 696, 10.1006/viro.1994.1233

Kleim, 1995, Preclinical evaluation of HBY 097, a new nonnucleoside reverse transcriptase inhibitor of human immunodeficiency virus type 1 replication, Antimicrob. Agents Chemother., 39, 2253, 10.1128/AAC.39.10.2253

Kleim, 1996, Selective pressure of a quinoxaline nonnucleoside inhibitor of human immunodeficiency virus type 1 (HIV-1) reverse transcriptase (RT) on HIV-1 replication results in the emergence of nucleoside RT-inhibitor-specific (RT Leu-74→Val or Ile and Val-75→Leu or Ile) HIV-1 mutants, Proc. Natl. Acad. Sci. USA, 93, 34, 10.1073/pnas.93.1.34

Kleim, 1997, In vitro selection for different mutational patterns in the HIV-1 reverse transcriptase using high and low selective pressure of the nonnucleoside reverse transcriptase inhibitory HBY 097, Virology, 231, 112, 10.1006/viro.1997.8513

Koup, 1991, Inhibition of human immunodeficiency virus type 1 (HIV-1) replication by the dipyridodiazepinone BI-RG-587, J. Infect. Dis., 163, 966, 10.1093/infdis/163.5.966

Kroeger Smith, 1995, Molecular modeling studies of HIV-1 reverse transcriptase nonnucleoside inhibitors: total energy of complexation as a predictor of drug placement and activity, Protein Sci., 4, 2203, 10.1002/pro.5560041026

Larder, 1992, 3′-Azido-3′-deoxythymidine resistance suppressed by a mutation conferring human immunodeficiency virus type 1 resistance to nonnucleoside reverse transcriptase inhibitors, Antimicrob. Agents Chemother., 36, 2664, 10.1128/AAC.36.12.2664

Livermore, 1993, Synthesis and anti-HIV-1 activity of a series of imidazo[1,5-b]pyridazines, J. Med. Chem., 36, 3784, 10.1021/jm00076a005

Luzuriaga, 1997, Combination treatment with zidovudine, didanosine, and nevirapine in infants with human immunodeficiency virus type 1 infection, New Engl. J. Med., 336, 1343, 10.1056/NEJM199705083361902

Maass, 1993, Viral resistance to the thiazolo-iso-indolinones, a new class of nonnucleoside inhibitors of human immunodeficiency virus type 1 reverse transcriptase, Antimicrob. Agents Chemother., 37, 2612, 10.1128/AAC.37.12.2612

Marschner, 1998, Use of changes in plasma levels of human immunodeficiency virus type 1 RNA to assess the clinical benefit of antiretroviral therapy, J. Infect. Dis., 177, 40, 10.1086/513823

Massa, 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 Chem. Chemother., 6, 1, 10.1177/095632029500600101

Mayers, D., Riddler, S., Bach, M., Stein, D.F., Havlir, M.D., Kahn, J., Ruiz, N., Labriola, D.F. and the DMP 266 Clinical Development Team, 1997. Durable clinical anti-HIV-1 activity and tolerability for DMP 266 in combination with indinavir (IDV) at 24 weeks. 37th Annual Meeting of the Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC), Toronto, 30 September 1997, abstract I-175.

Mellors, 1992, In vitro selection and molecular characterization of human immunodeficiency virus-1 resistant to non-nucleoside inhibitors of reverse transcriptase, Mol. Pharmacol., 41, 446

Mellors, 1993, A single conservative amino acid substitution in the reverse transcriptase of human immunodeficiency virus-1 confers resistance to (+)-(5S)-4,5,6,7-tetrahydro-5-methyl-6-(3-methyl-2-butenyl)-imidazo[4,5,1-jk][1,4]benzodiazepin-2(1H)-thione (TIBO R82150), Mol. Pharmacol., 43, 11

Mellors, 1996, Prognosis in HIV-1 infection predicted by the quantity of virus in plasma, Science, 272, 1167, 10.1126/science.272.5265.1167

Merluzzi, 1990, Inhibition of HIV-1 replication by a nonnucleoside reverse transcriptase inhibitor, Science, 250, 1411, 10.1126/science.1701568

Mertens, 1993, Selective non-nucleoside HIV-1 reverse transcriptase inhibitors. New 2,3-dihydrothiazolo[2,3-a]isoindol-5(9H)-ones and related compounds with anti-HIV-1 activity, J. Med. Chem., 36, 2526, 10.1021/jm00069a011

Miyasaka, 1989, A novel lead for specific anti-HIV-1 agents: 1-[(2-hydroxyethoxy)methyl]-6-(phenylthio)thymine, J. Med. Chem., 32, 2507, 10.1021/jm00132a002

Moxham, 1997, Preliminary efficacy, pharmacokinetics and safety of repeated multiple doses of MKC-442 in HIV-infected volunteers. Abstracts of the Tenth International Conference on Antiviral Research, Atlanta, GA, 6–11 April 1997, Antiviral Res., 34, A44, 10.1016/S0166-3542(97)83151-8

Nunberg, 1991, Viral resistance to human immunodeficiency virus type 1-specific pyridinone reverse transcriptase inhibitors, J. Virol., 65, 4887, 10.1128/JVI.65.9.4887-4892.1991

O'Brien, 1996, Changes in plasma HIV-1 RNA and CD4+ lymphocyte counts and the risk of progression to AIDS, New Engl. J. Med., 334, 426, 10.1056/NEJM199602153340703

Okamoto, 1996, Complete inhibition of viral breakthrough by combination of MKC-442 with AZT during a long-term culture of HIV-1-infected cells, Antiviral Res., 31, 69, 10.1016/0166-3542(96)00946-1

Pagano, 1995, In vitro inhibition of human immunodeficiency virus type 1 by a combination of delavirdine (U-90152) with protease inhibitor U-75875 or interferon-α, J. Infect. Dis., 171, 61, 10.1093/infdis/171.1.61

Pantaleo, 1995, Studies in subjects with long-term nonprogressive human immunodeficiency virus infection, New Engl. J. Med., 332, 209, 10.1056/NEJM199501263320402

Pauwels, 1990, Potent and selective inhibition of HIV-1 replication in vitro by a novel series of TIBO derivatives, Nature, 343, 470, 10.1038/343470a0

Pauwels, 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, Proc. Natl. Acad. Sci. USA, 90, 1711, 10.1073/pnas.90.5.1711

Pauwels, 1994, New tetrahydroimidazo[4,5,1-jk][1,4]-benzodiazepin-2(1H)-one and -thione derivatives are potent inhibitors of human immunodeficiency virus type 1 replication and are synergistic with 2′,3′-dideoxynucleoside analogs, Antimicrob. Agents Chemother., 38, 2863, 10.1128/AAC.38.12.2863

Pelemans, 1997, Characteristics of the Pro225His mutation in human immunodeficiency virus type 1 (HIV-1) reverse transcriptase that appears under selective pressure of dose-escalating quinoxaline treatment of HIV-1, J. Virol., 71, 8195, 10.1128/JVI.71.11.8195-8203.1997

Perelson, 1996, HIV-1 dynamics in vivo: virion clearance rate, infected cell life-span, and viral generation time, Science, 271, 1582, 10.1126/science.271.5255.1582

Pialoux, 1991, Pharmacokinetics of R 82913 in patients with AIDS or AIDS-related complex, Lancet, 338, 140, 10.1016/0140-6736(91)90135-C

Ren, 1995, High resolution structures of HIV-1 RT from four RT-inhibitor complexes, Struct. Biol., 2, 293, 10.1038/nsb0495-293

Ren, 1995, The structure of HIV-1 reverse transcriptase complexed with 9-chloro-TIBO: lessons for inhibitor design, Structure, 3, 915, 10.1016/S0969-2126(01)00226-X

Richman, 1991, Human immunodeficiency virus type 1 mutants resistant to nonnucleoside inhibitors of reverse transcriptase arise in tissue culture, Proc. Natl. Acad. Sci. USA, 88, 11241, 10.1073/pnas.88.24.11241

Richman, 1991, BI-RG-587 is active against zidovudine-resistant human immunodeficiency virus type 1 and synergistic with zidovudine, Antimicrob. Agents Chemother., 35, 305, 10.1128/AAC.35.2.305

Richman, 1994, Nevirapine resistance mutations of human immunodeficiency virus type 1 selected during therapy, J. Virol., 68, 1660, 10.1128/JVI.68.3.1660-1666.1994

Romero, 1991, Nonnucleoside reverse transcriptase inhibitors that potently and specifically block human immunodeficiency virus type 1 replication, Proc. Natl. Acad. Sci. USA, 88, 8806, 10.1073/pnas.88.19.8806

Romero, 1993, Bis(heteroaryl)piperazine (BHAP) reverse transcriptase inhibitors: structure–activity relationships of novel substituted indole analogues and the identification of 1-[(5-methanesulfonamido-1H-indol-2-yl)carbonyl]-4-[3-[(1-methylethyl)amino]pyridinyl]piperazine monomethanesulfonate (U-90152S), a second-generation clinical candidate, J. Med. Chem., 36, 1505, 10.1021/jm00062a027

Rübsamen-Waigmann, 1997, Second-generation non-nucleoside reverse transcriptase inhibitor HBY 097 and HIV-1 viral load, Lancet, 349, 1517, 10.1016/S0140-6736(97)24021-3

Saag, 1993, A short-term clinical evaluation of L-697,661, a non-nucleoside inhibitor of HIV-1 reverse transcriptase, New Engl. J. Med., 329, 1065, 10.1056/NEJM199310073291502

Saag, 1996, HIV viral load markers in clinical practice, Nat. Med., 2, 625, 10.1038/nm0696-625

Sahai, 1996, Risks and synergies from drug interactions, AIDS, 10, S21

Schinazi, 1997, Mutations in retroviral genes associated with drug resistance, Int. Antiviral News, 5, 129

Schooley, 1996, Phase 1 study of combination therapy with L-697,661 and zidovudine, J. Acquired Immune Defic. Syndr. Hum. Retrovirol., 12, 363, 10.1097/00042560-199608010-00006

Seki, 1995, Isolation and characterization of human immunodeficiency virus type-1 mutants resistant to the non-nucleotide reverse transcriptase inhibitor MKC-442, Antiviral Chem. Chemother., 6, 73, 10.1177/095632029500600201

Silvestri, 1998, Synthesis and biological evaluation of 5H-indolo [3,2-b][1,5]benzothiazepine derivatives, designed as conformationally constrained analogues of the human immunodeficiency virus type 1 reverse transcriptase inhibitor L-737,126, Antiviral Chem. Chemother., 9, 139, 10.1177/095632029800900205

Skowron, G., Leoung, G., Dusek, A., Anderson, R., Grosso, R., Jacobs, M., Lamson, M., Kerr, B., Beebe, S., 1998. dNN study: stavudine (d4T), nelfinavir (NFV), and nevirapine (NVP): preliminary safety, activity, and pharmacokinetic (PK) interactions. 5th Conference on Retroviruses and Opportunistic Infections, Chicago, IL, 1–5 February 1998, abstract 350.

Spence, 1995, Mechanism of inhibition of HIV-1 reverse transcriptase by nonnucleoside inhibitors, Science, 267, 988, 10.1126/science.7532321

Staszewski, 1995, Combination therapy with zidovudine prevents selection of human immunodeficiency virus type 1 variants expressing high level resistance to L-697,661, a non-nucleoside reverse transcriptase inhibitor, J. Infect. Dis., 171, 159, 10.1093/infdis/171.5.1159

Staszewski, 1996, Evaluation of the efficacy and tolerance of R 018893, R 089439 (loviride) and placebo in asymptomatic HIV-1-infected patients, Antiviral Ther., 1, 42

Staszewski, 1996, Virological and immunological analysis of a triple combination pilot study with loviride, lamivudine and zidovudine in HIV-1-infected patients, AIDS, 10, F1, 10.1097/00002030-199605000-00001

Tantillo, 1994, Locations of anti-AIDS drug binding sites and resistance mutations in the three-dimensional structure of HIV-1 reverse transcriptase, J. Mol. Biol., 243, 369, 10.1006/jmbi.1994.1665

Terrett, 1992, Imidazo[2′,3′:6,5]dipyrido[3,2-b:2′,3′-e]-1,4-diazepines: non-nucleoside HIV-1 reverse transcriptase inhibitors with greater enzyme affinity than nevirapine, Bioorg. Med. Chem. Lett., 2, 1745, 10.1016/S0960-894X(00)80468-0

Tucker, 1994, Synthesis of a series of 4-(arylethynyl)-6-chloro-4-cyclopropyl-3,4-dihydroquinazolin-2(1H)-ones as novel non-nucleoside HIV-1 reverse transcriptase inhibitors, J. Med. Chem., 37, 2437, 10.1021/jm00041a023

Vasudevachari, 1992, Prevention of the spread of HIV-1 infection with nonnucleoside reverse transcriptase inhibitors, Virology, 190, 269, 10.1016/0042-6822(92)91213-E

Wainberg, 1996, Enhanced fidelity of 3TC-selected mutant HIV-1 reverse transcriptase, Science, 271, 1282, 10.1126/science.271.5253.1282

Wei, 1995, Viral dynamics in human immunodeficiency virus type 1 infection, Nature, 373, 117, 10.1038/373117a0

Williams, 1993, 5-Chloro-3-(phenylsulfonyl)indole-2-caboxamide: a novel, non-nucleoside inhibitor of HIV-1 reverse transcriptase, J. Med. Chem., 36, 1291, 10.1021/jm00061a022

Winslow, 1996, Selection conditions affect the evolution of specific mutations in the reverse transcriptase gene associated with resistance to DMP 266, AIDS, 10, 1205, 10.1097/00002030-199609000-00005

Witvrouw, 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 (NNRTIs) with anti-HIV-1 activity, Antimicrob. Agents Chemother., 42, 618, 10.1128/AAC.42.3.618

Wong, 1997, Recovery of replication-competent HIV despite prolonged suppression of plasma viremia, Science, 278, 1291, 10.1126/science.278.5341.1291

Young, 1995, L-743,726 (DMP-266): a novel, highly potent nonnucleoside inhibitor of the human immunodeficiency virus type 1 reverse transcriptase, Antimicrob. Agents Chemother., 39, 2602, 10.1128/AAC.39.12.2602

Yuasa, 1993, Selective and synergistic inhibition of human immunodeficiency virus type 1 reverse transcriptase by a non-nucleoside inhibitor, MKC-442, Mol. Pharmacol., 44, 895

Zembower, 1997, Structural analogues of the calanolide anti-HIV agents. Modification of the trans-10,11-dimethyldihydropyran-12-ol ring (ring C), J. Med. Chem., 40, 1005, 10.1021/jm960355m

Zhang, 1995, Inhibition of human immunodeficiency virus type 1 wild-type and mutant reverse transcriptases by the phenyl ethyl thiazolyl thiourea derivatives trovirdine and MSC-127, Antiviral Res., 28, 331, 10.1016/0166-3542(95)00056-9