Antiviral activity of the dihydropyrone PNU-140690, a new nonpeptidic human immunodeficiency virus protease inhibitor

PNU-140690 is a member of a new class of nonpeptidic human immunodeficiency virus (HIV) protease inhibitors (sulfonamide-containing 5,6-dihydro-4-hydroxy-2-pyrones) discovered by structure-based design. PNU-140690 has excellent potency against a variety of HIV type 1 (HIV-1) laboratory strains and clinical isolates, including those resistant to the reverse transcriptase inhibitors zidovudine or delavirdine. When combined with either zidovudine or delavirdine, PNU-140690 contributes to synergistic antiviral activity. PNU-140690 is also highly active against HIV-1 variants resistant to peptidomimetic protease inhibitors, underscoring the structural distinctions between PNU-140690 and substrate analog protease inhibitors. PNU-140690 retains good antiviral activity in vitro in the presence of human plasma proteins, and preclinical pharmacokinetic studies revealed good oral bioavailability. Accordingly, PNU-140690 is a candidate for clinical evaluation.

[1]  J. Condra,et al.  In vivo emergence of HIV-1 variants resistant to multiple protease inhibitors , 1995, Nature.

[2]  I. Chen,et al.  A mutation in reverse transcriptase of bis(heteroaryl)piperazine-resistant human immunodeficiency virus type 1 that confers increased sensitivity to other nonnucleoside inhibitors. , 1993, Proceedings of the National Academy of Sciences of the United States of America.

[3]  S D Kemp,et al.  Potential mechanism for sustained antiretroviral efficacy of AZT-3TC combination therapy. , 1995, Science.

[4]  L. Resnick,et al.  U-90152, a potent inhibitor of human immunodeficiency virus type 1 replication , 1993, Antimicrobial Agents and Chemotherapy.

[5]  W. Howe,et al.  Structure-based design of HIV protease inhibitors: sulfonamide-containing 5,6-dihydro-4-hydroxy-2-pyrones as non-peptidic inhibitors. , 1996, Journal of medicinal chemistry.

[6]  D. Ho,et al.  Selection and analysis of human immunodeficiency virus type 1 variants with increased resistance to ABT-538, a novel protease inhibitor , 1995, Journal of virology.

[7]  J. Coffin,et al.  HIV population dynamics in vivo: implications for genetic variation, pathogenesis, and therapy , 1995, Science.

[8]  K. Chong,et al.  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 , 1994, Antimicrobial Agents and Chemotherapy.

[9]  E A Emini,et al.  Viral resistance to human immunodeficiency virus type 1-specific pyridinone reverse transcriptase inhibitors , 1991, Journal of virology.

[10]  J. Bilello,et al.  Reduction of the in vitro activity of A77003, an inhibitor of human immunodeficiency virus protease, by human serum alpha 1 acid glycoprotein. , 1995, The Journal of infectious diseases.

[11]  D Norbeck,et al.  Characterization of human immunodeficiency virus type 1 variants with increased resistance to a C2-symmetric protease inhibitor , 1994, Journal of virology.

[12]  T. Mosmann.  Rapid colorimetric assay for cellular growth and survival: application to proliferation and cytotoxicity assays. , 1983, Journal of immunological methods.

[13]  E. De Clercq,et al.  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). , 1995, Proceedings of the National Academy of Sciences of the United States of America.

[14]  H. Mitsuya,et al.  Protein binding of human immunodeficiency virus protease inhibitor KNI-272 and alteration of its in vitro antiretroviral activity in the presence of high concentrations of proteins , 1994, Antimicrobial Agents and Chemotherapy.

[15]  T. Chou,et al.  Quantitative analysis of dose-effect relationships: the combined effects of multiple drugs or enzyme inhibitors. , 1984, Advances in enzyme regulation.

[16]  D. Richman.  Resistance of clinical isolates of human immunodeficiency virus to antiretroviral agents , 1993, Antimicrobial Agents and Chemotherapy.

[17]  L. Perrin,et al.  Therapeutic interventions in primary HIV infection. , 1995, Journal of acquired immune deficiency syndromes and human retrovirology : official publication of the International Retrovirology Association.

[18]  E D Blair,et al.  Cross-resistance analysis of human immunodeficiency virus type 1 variants individually selected for resistance to five different protease inhibitors , 1995, Antimicrobial agents and chemotherapy.

[19]  L. Resnick,et al.  Nonnucleoside reverse transcriptase inhibitors that potently and specifically block human immunodeficiency virus type 1 replication. , 1991, Proceedings of the National Academy of Sciences of the United States of America.

[20]  J. Barrish,et al.  Characterization of a human immunodeficiency virus type 1 variant with reduced sensitivity to an aminodiol protease inhibitor , 1995, Journal of virology.

[21]  D. Ho,et al.  Antiviral and resistance studies of AG1343, an orally bioavailable inhibitor of human immunodeficiency virus protease , 1996, Antimicrobial agents and chemotherapy.

[22]  B. Larder,et al.  Mutations in Retroviral Genes Associated with Drug Resistance , 1996 .

[23]  S. Vasavanonda,et al.  ABT-538 is a potent inhibitor of human immunodeficiency virus protease and has high oral bioavailability in humans. , 1995, Proceedings of the National Academy of Sciences of the United States of America.

[24]  B. Larder,et al.  Viral resistance and the selection of antiretroviral combinations. , 1995, Journal of acquired immune deficiency syndromes and human retrovirology : official publication of the International Retrovirology Association.

[25]  A. Perelson,et al.  Rapid turnover of plasma virions and CD4 lymphocytes in HIV-1 infection , 1995, Nature.

[26]  S D Kemp,et al.  Resistance to ddI and sensitivity to AZT induced by a mutation in HIV-1 reverse transcriptase. , 1991, Science.

[27]  V. Johnson,et al.  Standardized peripheral blood mononuclear cell culture assay for determination of drug susceptibilities of clinical human immunodeficiency virus type 1 isolates. The RV-43 Study Group, the AIDS Clinical Trials Group Virology Committee Resistance Working Group , 1993, Antimicrobial Agents and Chemotherapy.