Viracept (nelfinavir mesylate, AG1343): A potent, orally bioavailable inhibitor of HIV-1 protease

Journal of Medicinal Chemistry

Volumn 40, Issue 24, 1997, Pages 3979-3985

  Kaldor, Stephen W ^b   Kalish, Vincent J ^a   Davies II, Jay F ^a   Shetty, Bhasker V ^a   Fritz, James E ^a   Appelt, Krzysztof ^a   Burgess, Jeffrey A ^b   Campanale, Kristina M ^b   Chirgadze, Nickolay Y ^b   Clawson, David K ^b   Dressman, Bruce A ^b   Hatch, Steven D ^b   Khalil, Deborah A ^a   Kosa, Maha B ^a   Lubbehusen, Penny P ^b   Muesing, Mark A ^b   Patick, Amy K ^a   Reich, Siegfried H ^a   Su, Kenneth S ^b   Tatlock, John H ^a  

^a AGOURON PHARMACEUTICALS INC   (United States)

^b ELI LILLY AND COMPANY   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

ANTIVIRUS AGENT; NELFINAVIR; PROTEINASE; PROTEINASE INHIBITOR;

ACQUIRED IMMUNE DEFICIENCY SYNDROME; AREA UNDER THE CURVE; ARTICLE; CLINICAL TRIAL; CRYSTAL STRUCTURE; DOG; DRUG ABSORPTION; DRUG PROTEIN BINDING; DRUG SYNTHESIS; HUMAN; HUMAN IMMUNODEFICIENCY VIRUS 1; INTRAVENOUS DRUG ADMINISTRATION; MARMOSET; NONHUMAN; ORAL DRUG ADMINISTRATION; RAT;

ADMINISTRATION, ORAL; ANIMALS; ANTI-HIV AGENTS; BIOLOGICAL AVAILABILITY; CALLITHRIX; DOGS; DOSE-RESPONSE RELATIONSHIP, DRUG; FEMALE; HIV PROTEASE INHIBITORS; HIV-1; MACACA FASCICULARIS; MALE; NELFINAVIR; RATS; RATS, SPRAGUE-DAWLEY; STRUCTURE-ACTIVITY RELATIONSHIP;

EID: 14444281534     PISSN: 00222623     EISSN: None     Source Type: Journal    
DOI: 10.1021/jm9704098     Document Type: Article

References (33)

1. For recent reviews, see: (a) Huff, J. R. HIV Protease: A Novel Chemotherapeutic Target for AIDS. J. Med. Chem. 1991, 34, 2305-2314. (b) Thaisrivongs, S. HIV Protease Inhibitors. Annual Reports in Medicinal Chemistry; Bristol, J. A., Ed.; Academic Press: New York, 1994; Vol. 29, pp 133-144. Darke, P. L.; Huff, J. R. HIV Protease as an Inhibitor Target for the Treatment of AIDS. Advances in Pharmacology; August, J. T., Anders, M. W., Murad, F., Eds.; Academic Press: San Diego, 1994; Vol. 25, pp 399-454. West, M. L.; Fairlie, D. P. Targeting HIV-1 Protease: A Test of Drug-Design Methodologies. Trends Pharm. Sci. 1995, 16, 67-75.
2. For recent reviews, see: (a) Huff, J. R. HIV Protease: A Novel Chemotherapeutic Target for AIDS. J. Med. Chem. 1991, 34, 2305-2314. (b) Thaisrivongs, S. HIV Protease Inhibitors. Annual Reports in Medicinal Chemistry; Bristol, J. A., Ed.; Academic Press: New York, 1994; Vol. 29, pp 133-144. Darke, P. L.; Huff, J. R. HIV Protease as an Inhibitor Target for the Treatment of AIDS. Advances in Pharmacology; August, J. T., Anders, M. W., Murad, F., Eds.; Academic Press: San Diego, 1994; Vol. 25, pp 399-454. West, M. L.; Fairlie, D. P. Targeting HIV-1 Protease: A Test of Drug-Design Methodologies. Trends Pharm. Sci. 1995, 16, 67-75.
3. For recent reviews, see: (a) Huff, J. R. HIV Protease: A Novel Chemotherapeutic Target for AIDS. J. Med. Chem. 1991, 34, 2305-2314. (b) Thaisrivongs, S. HIV Protease Inhibitors. Annual Reports in Medicinal Chemistry; Bristol, J. A., Ed.; Academic Press: New York, 1994; Vol. 29, pp 133-144. Darke, P. L.; Huff, J. R. HIV Protease as an Inhibitor Target for the Treatment of AIDS. Advances in Pharmacology; August, J. T., Anders, M. W., Murad, F., Eds.; Academic Press: San Diego, 1994; Vol. 25, pp 399-454. West, M. L.; Fairlie, D. P. Targeting HIV-1 Protease: A Test of Drug-Design Methodologies. Trends Pharm. Sci. 1995, 16, 67-75.
4. For recent reviews, see: (a) Huff, J. R. HIV Protease: A Novel Chemotherapeutic Target for AIDS. J. Med. Chem. 1991, 34, 2305-2314. (b) Thaisrivongs, S. HIV Protease Inhibitors. Annual Reports in Medicinal Chemistry; Bristol, J. A., Ed.; Academic Press: New York, 1994; Vol. 29, pp 133-144. Darke, P. L.; Huff, J. R. HIV Protease as an Inhibitor Target for the Treatment of AIDS. Advances in Pharmacology; August, J. T., Anders, M. W., Murad, F., Eds.; Academic Press: San Diego, 1994; Vol. 25, pp 399-454. West, M. L.; Fairlie, D. P. Targeting HIV-1 Protease: A Test of Drug-Design Methodologies. Trends Pharm. Sci. 1995, 16, 67-75.
5. HIV-1 protease inhibitors tested in clinical trials include: (a) Ro 31-8959: Roberts, N. A.; Martin, J. A.; Kinchington, D.; Broadhurst, A. V.; Craig, J. C.; Duncan, I. B.; Galpin, S. A.; Handa, B. K.; Kay, J.; Krohn, A.; Lambert, R. W.; Merrett, J. H.; Mills, J. S.; Parkes, K. E. B.; Redshaw, S.; Ritchie, A. J.; Taylor, D.L.; Thomas, G. J.; Machin, P. J. Rational Design of Peptide-Based HIV Proteinase Inhibitors. Science 1990, 248, 358-361. (b) L-735,524: Vacca, J. P.; Dorsey, B. D.; Schleif, W. A.; Levin, R. B.; McDaniel, S. L.; Darke, P. L.; Zugay, J.; Quintero, J. C.; Blahy, O. M.; Roth, E.; Sardana, V. V.; Schlabach, A. J.; Graham, P. I.; Condra, J. H.; Gotlib, L.; Holloway, M. K.; Lin, J.; Chen, I.-W.; Vastag, K.; Ostovic, D.; Andersen, P. S.; Emini, E. A.; Huff, J. R. L-735,524: An Orally Bioavailable Human Immunodeficiency Virus Type 1 Protease Inhibitor. Proc. Natl. Acad. Sci. U.S.A. 1994, 91, 4096-4100. XM-412: Wong, Y. N Biopharm. Drug Dispos. 1995, 15, 535-544. U96988: Thaisrivongs, S.; Tomich, P. K.; Watenpaugh, K. D.; Chong, K. T.; Howe, W. J.; Yang, C.-P.; Strohbach, J. W.; Turner, S. R.; McGrath, J. P.; Bohanon, M. J.; Lynn, J. C.; Mulichak, A. M.; Spinelli, P. A.; Hinshaw, R. R.; Pagano, P. J.; Moon, J. B.; Ruwart, M. J.; Wilkinson, K. F.; Rush, B. D.; Zipp, G. L.; Dalga, R. J.; Schwende, F. J.; Howard, G. M.; Padbury, G. E.; Toth, L. N.; Zhao, Z.; Koeplinger, K. A.; Kakuk, T. J.; Cole, S. L.; Zaya, R. M.; Piper, R. C.; Jeffrey, P. Structure-Based Design of HIV Protease Inhibitors: 4-Hydroxycoumarins and 4-Hydroxy-2-Pyrones as Non-peptidic Inhibitors. J. Med. Chem. 1994, 37, 3200-3204. (e) VX-478: Kim, E. E.; Baker, C. T.; Dwyer, M. ID.; Murko, M. A.; Rao, B. G.; Tung, R. D.; Navia, M. R. Crystal Structure of HIV-1 Protease in Complex with VX-478, a Potent and Orally Bioavailable Inhibitor of the Enzyme. J. Am. Chem. Soc. 1995, 117, 1181-1182. (f) ABT-538: Kempf, D. J.; Marsh, K. C.; Denissen, J.; McDonald, E.; Vasavanonda, S.; Flengte, C.; Green, B. E.; Fino, L.; Park, C.; Kong, X.; Wideburg, N. E.; Saldivar, A.; Ruiz, L.; Kati, W. M.; Sham, H. L.; Robins, T.; Stewart, K. D.; Hsu, A.; Plattner, J. J.; Leonard, J. M.; Norbeck, D. W. ABT-538 is a Potent Inhibitor of Human Immunodefi- ciency Virus Protease and has High Oral Bioavailability in Humans. Proc. Natl. Acad. Sci. U.S.A. 1995, 92, 2484-2488.
6. HIV-1 protease inhibitors tested in clinical trials include: (a) Ro 31-8959: Roberts, N. A.; Martin, J. A.; Kinchington, D.; Broadhurst, A. V.; Craig, J. C.; Duncan, I. B.; Galpin, S. A.; Handa, B. K.; Kay, J.; Krohn, A.; Lambert, R. W.; Merrett, J. H.; Mills, J. S.; Parkes, K. E. B.; Redshaw, S.; Ritchie, A. J.; Taylor, D.L.; Thomas, G. J.; Machin, P. J. Rational Design of Peptide-Based HIV Proteinase Inhibitors. Science 1990, 248, 358-361. (b) L-735,524: Vacca, J. P.; Dorsey, B. D.; Schleif, W. A.; Levin, R. B.; McDaniel, S. L.; Darke, P. L.; Zugay, J.; Quintero, J. C.; Blahy, O. M.; Roth, E.; Sardana, V. V.; Schlabach, A. J.; Graham, P. I.; Condra, J. H.; Gotlib, L.; Holloway, M. K.; Lin, J.; Chen, I.-W.; Vastag, K.; Ostovic, D.; Andersen, P. S.; Emini, E. A.; Huff, J. R. L-735,524: An Orally Bioavailable Human Immunodeficiency Virus Type 1 Protease Inhibitor. Proc. Natl. Acad. Sci. U.S.A. 1994, 91, 4096-4100. XM-412: Wong, Y. N Biopharm. Drug Dispos. 1995, 15, 535-544. U96988: Thaisrivongs, S.; Tomich, P. K.; Watenpaugh, K. D.; Chong, K. T.; Howe, W. J.; Yang, C.-P.; Strohbach, J. W.; Turner, S. R.; McGrath, J. P.; Bohanon, M. J.; Lynn, J. C.; Mulichak, A. M.; Spinelli, P. A.; Hinshaw, R. R.; Pagano, P. J.; Moon, J. B.; Ruwart, M. J.; Wilkinson, K. F.; Rush, B. D.; Zipp, G. L.; Dalga, R. J.; Schwende, F. J.; Howard, G. M.; Padbury, G. E.; Toth, L. N.; Zhao, Z.; Koeplinger, K. A.; Kakuk, T. J.; Cole, S. L.; Zaya, R. M.; Piper, R. C.; Jeffrey, P. Structure-Based Design of HIV Protease Inhibitors: 4-Hydroxycoumarins and 4-Hydroxy-2-Pyrones as Non-peptidic Inhibitors. J. Med. Chem. 1994, 37, 3200-3204. (e) VX-478: Kim, E. E.; Baker, C. T.; Dwyer, M. ID.; Murko, M. A.; Rao, B. G.; Tung, R. D.; Navia, M. R. Crystal Structure of HIV-1 Protease in Complex with VX-478, a Potent and Orally Bioavailable Inhibitor of the Enzyme. J. Am. Chem. Soc. 1995, 117, 1181-1182. (f) ABT-538: Kempf, D. J.; Marsh, K. C.; Denissen, J.; McDonald, E.; Vasavanonda, S.; Flengte, C.; Green, B. E.; Fino, L.; Park, C.; Kong, X.; Wideburg, N. E.; Saldivar, A.; Ruiz, L.; Kati, W. M.; Sham, H. L.; Robins, T.; Stewart, K. D.; Hsu, A.; Plattner, J. J.; Leonard, J. M.; Norbeck, D. W. ABT-538 is a Potent Inhibitor of Human Immunodeficiency Virus Protease and has High Oral Bioavailability in Humans. Proc. Natl. Acad. Sci. U.S.A. 1995, 92, 2484-2488.
7. HIV-1 protease inhibitors tested in clinical trials include: (a) Ro 31-8959: Roberts, N. A.; Martin, J. A.; Kinchington, D.; Broadhurst, A. V.; Craig, J. C.; Duncan, I. B.; Galpin, S. A.; Handa, B. K.; Kay, J.; Krohn, A.; Lambert, R. W.; Merrett, J. H.; Mills, J. S.; Parkes, K. E. B.; Redshaw, S.; Ritchie, A. J.; Taylor, D.L.; Thomas, G. J.; Machin, P. J. Rational Design of Peptide-Based HIV Proteinase Inhibitors. Science 1990, 248, 358-361. (b) L-735,524: Vacca, J. P.; Dorsey, B. D.; Schleif, W. A.; Levin, R. B.; McDaniel, S. L.; Darke, P. L.; Zugay, J.; Quintero, J. C.; Blahy, O. M.; Roth, E.; Sardana, V. V.; Schlabach, A. J.; Graham, P. I.; Condra, J. H.; Gotlib, L.; Holloway, M. K.; Lin, J.; Chen, I.-W.; Vastag, K.; Ostovic, D.; Andersen, P. S.; Emini, E. A.; Huff, J. R. L-735,524: An Orally Bioavailable Human Immunodeficiency Virus Type 1 Protease Inhibitor. Proc. Natl. Acad. Sci. U.S.A. 1994, 91, 4096-4100. XM-412: Wong, Y. N Biopharm. Drug Dispos. 1995, 15, 535-544. U96988: Thaisrivongs, S.; Tomich, P. K.; Watenpaugh, K. D.; Chong, K. T.; Howe, W. J.; Yang, C.-P.; Strohbach, J. W.; Turner, S. R.; McGrath, J. P.; Bohanon, M. J.; Lynn, J. C.; Mulichak, A. M.; Spinelli, P. A.; Hinshaw, R. R.; Pagano, P. J.; Moon, J. B.; Ruwart, M. J.; Wilkinson, K. F.; Rush, B. D.; Zipp, G. L.; Dalga, R. J.; Schwende, F. J.; Howard, G. M.; Padbury, G. E.; Toth, L. N.; Zhao, Z.; Koeplinger, K. A.; Kakuk, T. J.; Cole, S. L.; Zaya, R. M.; Piper, R. C.; Jeffrey, P. Structure-Based Design of HIV Protease Inhibitors: 4-Hydroxycoumarins and 4-Hydroxy-2-Pyrones as Non-peptidic Inhibitors. J. Med. Chem. 1994, 37, 3200-3204. (e) VX-478: Kim, E. E.; Baker, C. T.; Dwyer, M. ID.; Murko, M. A.; Rao, B. G.; Tung, R. D.; Navia, M. R. Crystal Structure of HIV-1 Protease in Complex with VX-478, a Potent and Orally Bioavailable Inhibitor of the Enzyme. J. Am. Chem. Soc. 1995, 117, 1181-1182. (f) ABT-538: Kempf, D. J.; Marsh, K. C.; Denissen, J.; McDonald, E.; Vasavanonda, S.; Flengte, C.; Green, B. E.; Fino, L.; Park, C.; Kong, X.; Wideburg, N. E.; Saldivar, A.; Ruiz, L.; Kati, W. M.; Sham, H. L.; Robins, T.; Stewart, K. D.; Hsu, A.; Plattner, J. J.; Leonard, J. M.; Norbeck, D. W. ABT-538 is a Potent Inhibitor of Human Immunodefi- ciency Virus Protease and has High Oral Bioavailability in Humans. Proc. Natl. Acad. Sci. U.S.A. 1995, 92, 2484-2488.
8. HIV-1 protease inhibitors tested in clinical trials include: (a) Ro 31-8959: Roberts, N. A.; Martin, J. A.; Kinchington, D.; Broadhurst, A. V.; Craig, J. C.; Duncan, I. B.; Galpin, S. A.; Handa, B. K.; Kay, J.; Krohn, A.; Lambert, R. W.; Merrett, J. H.; Mills, J. S.; Parkes, K. E. B.; Redshaw, S.; Ritchie, A. J.; Taylor, D.L.; Thomas, G. J.; Machin, P. J. Rational Design of Peptide-Based HIV Proteinase Inhibitors. Science 1990, 248, 358-361. (b) L-735,524: Vacca, J. P.; Dorsey, B. D.; Schleif, W. A.; Levin, R. B.; McDaniel, S. L.; Darke, P. L.; Zugay, J.; Quintero, J. C.; Blahy, O. M.; Roth, E.; Sardana, V. V.; Schlabach, A. J.; Graham, P. I.; Condra, J. H.; Gotlib, L.; Holloway, M. K.; Lin, J.; Chen, I.-W.; Vastag, K.; Ostovic, D.; Andersen, P. S.; Emini, E. A.; Huff, J. R. L-735,524: An Orally Bioavailable Human Immunodeficiency Virus Type 1 Protease Inhibitor. Proc. Natl. Acad. Sci. U.S.A. 1994, 91, 4096-4100. XM-412: Wong, Y. N Biopharm. Drug Dispos. 1995, 15, 535-544. U96988: Thaisrivongs, S.; Tomich, P. K.; Watenpaugh, K. D.; Chong, K. T.; Howe, W. J.; Yang, C.-P.; Strohbach, J. W.; Turner, S. R.; McGrath, J. P.; Bohanon, M. J.; Lynn, J. C.; Mulichak, A. M.; Spinelli, P. A.; Hinshaw, R. R.; Pagano, P. J.; Moon, J. B.; Ruwart, M. J.; Wilkinson, K. F.; Rush, B. D.; Zipp, G. L.; Dalga, R. J.; Schwende, F. J.; Howard, G. M.; Padbury, G. E.; Toth, L. N.; Zhao, Z.; Koeplinger, K. A.; Kakuk, T. J.; Cole, S. L.; Zaya, R. M.; Piper, R. C.; Jeffrey, P. Structure-Based Design of HIV Protease Inhibitors: 4-Hydroxycoumarins and 4-Hydroxy-2-Pyrones as Non-peptidic Inhibitors. J. Med. Chem. 1994, 37, 3200-3204. (e) VX-478: Kim, E. E.; Baker, C. T.; Dwyer, M. ID.; Murko, M. A.; Rao, B. G.; Tung, R. D.; Navia, M. R. Crystal Structure of HIV-1 Protease in Complex with VX-478, a Potent and Orally Bioavailable Inhibitor of the Enzyme. J. Am. Chem. Soc. 1995, 117, 1181-1182. (f) ABT-538: Kempf, D. J.; Marsh, K. C.; Denissen, J.; McDonald, E.; Vasavanonda, S.; Flengte, C.; Green, B. E.; Fino, L.; Park, C.; Kong, X.; Wideburg, N. E.; Saldivar, A.; Ruiz, L.; Kati, W. M.; Sham, H. L.; Robins, T.; Stewart, K. D.; Hsu, A.; Plattner, J. J.; Leonard, J. M.; Norbeck, D. W. ABT-538 is a Potent Inhibitor of Human Immunodefi- ciency Virus Protease and has High Oral Bioavailability in Humans. Proc. Natl. Acad. Sci. U.S.A. 1995, 92, 2484-2488.
9. HIV-1 protease inhibitors tested in clinical trials include: (a) Ro 31-8959: Roberts, N. A.; Martin, J. A.; Kinchington, D.; Broadhurst, A. V.; Craig, J. C.; Duncan, I. B.; Galpin, S. A.; Handa, B. K.; Kay, J.; Krohn, A.; Lambert, R. W.; Merrett, J. H.; Mills, J. S.; Parkes, K. E. B.; Redshaw, S.; Ritchie, A. J.; Taylor, D.L.; Thomas, G. J.; Machin, P. J. Rational Design of Peptide-Based HIV Proteinase Inhibitors. Science 1990, 248, 358-361. (b) L-735,524: Vacca, J. P.; Dorsey, B. D.; Schleif, W. A.; Levin, R. B.; McDaniel, S. L.; Darke, P. L.; Zugay, J.; Quintero, J. C.; Blahy, O. M.; Roth, E.; Sardana, V. V.; Schlabach, A. J.; Graham, P. I.; Condra, J. H.; Gotlib, L.; Holloway, M. K.; Lin, J.; Chen, I.-W.; Vastag, K.; Ostovic, D.; Andersen, P. S.; Emini, E. A.; Huff, J. R. L-735,524: An Orally Bioavailable Human Immunodeficiency Virus Type 1 Protease Inhibitor. Proc. Natl. Acad. Sci. U.S.A. 1994, 91, 4096-4100. XM-412: Wong, Y. N Biopharm. Drug Dispos. 1995, 15, 535-544. U96988: Thaisrivongs, S.; Tomich, P. K.; Watenpaugh, K. D.; Chong, K. T.; Howe, W. J.; Yang, C.-P.; Strohbach, J. W.; Turner, S. R.; McGrath, J. P.; Bohanon, M. J.; Lynn, J. C.; Mulichak, A. M.; Spinelli, P. A.; Hinshaw, R. R.; Pagano, P. J.; Moon, J. B.; Ruwart, M. J.; Wilkinson, K. F.; Rush, B. D.; Zipp, G. L.; Dalga, R. J.; Schwende, F. J.; Howard, G. M.; Padbury, G. E.; Toth, L. N.; Zhao, Z.; Koeplinger, K. A.; Kakuk, T. J.; Cole, S. L.; Zaya, R. M.; Piper, R. C.; Jeffrey, P. Structure-Based Design of HIV Protease Inhibitors: 4-Hydroxycoumarins and 4-Hydroxy-2-Pyrones as Non-peptidic Inhibitors. J. Med. Chem. 1994, 37, 3200-3204. (e) VX-478: Kim, E. E.; Baker, C. T.; Dwyer, M. ID.; Murko, M. A.; Rao, B. G.; Tung, R. D.; Navia, M. R. Crystal Structure of HIV-1 Protease in Complex with VX-478, a Potent and Orally Bioavailable Inhibitor of the Enzyme. J. Am. Chem. Soc. 1995, 117, 1181-1182. (f) ABT-538: Kempf, D. J.; Marsh, K. C.; Denissen, J.; McDonald, E.; Vasavanonda, S.; Flengte, C.; Green, B. E.; Fino, L.; Park, C.; Kong, X.; Wideburg, N. E.; Saldivar, A.; Ruiz, L.; Kati, W. M.; Sham, H. L.; Robins, T.; Stewart, K. D.; Hsu, A.; Plattner, J. J.; Leonard, J. M.; Norbeck, D. W. ABT-538 is a Potent Inhibitor of Human Immunodefi- ciency Virus Protease and has High Oral Bioavailability in Humans. Proc. Natl. Acad. Sci. U.S.A. 1995, 92, 2484-2488.
10. HIV-1 protease inhibitors tested in clinical trials include: (a) Ro 31-8959: Roberts, N. A.; Martin, J. A.; Kinchington, D.; Broadhurst, A. V.; Craig, J. C.; Duncan, I. B.; Galpin, S. A.; Handa, B. K.; Kay, J.; Krohn, A.; Lambert, R. W.; Merrett, J. H.; Mills, J. S.; Parkes, K. E. B.; Redshaw, S.; Ritchie, A. J.; Taylor, D.L.; Thomas, G. J.; Machin, P. J. Rational Design of Peptide-Based HIV Proteinase Inhibitors. Science 1990, 248, 358-361. (b) L-735,524: Vacca, J. P.; Dorsey, B. D.; Schleif, W. A.; Levin, R. B.; McDaniel, S. L.; Darke, P. L.; Zugay, J.; Quintero, J. C.; Blahy, O. M.; Roth, E.; Sardana, V. V.; Schlabach, A. J.; Graham, P. I.; Condra, J. H.; Gotlib, L.; Holloway, M. K.; Lin, J.; Chen, I.-W.; Vastag, K.; Ostovic, D.; Andersen, P. S.; Emini, E. A.; Huff, J. R. L-735,524: An Orally Bioavailable Human Immunodeficiency Virus Type 1 Protease Inhibitor. Proc. Natl. Acad. Sci. U.S.A. 1994, 91, 4096-4100. XM-412: Wong, Y. N Biopharm. Drug Dispos. 1995, 15, 535-544. U96988: Thaisrivongs, S.; Tomich, P. K.; Watenpaugh, K. D.; Chong, K. T.; Howe, W. J.; Yang, C.-P.; Strohbach, J. W.; Turner, S. R.; McGrath, J. P.; Bohanon, M. J.; Lynn, J. C.; Mulichak, A. M.; Spinelli, P. A.; Hinshaw, R. R.; Pagano, P. J.; Moon, J. B.; Ruwart, M. J.; Wilkinson, K. F.; Rush, B. D.; Zipp, G. L.; Dalga, R. J.; Schwende, F. J.; Howard, G. M.; Padbury, G. E.; Toth, L. N.; Zhao, Z.; Koeplinger, K. A.; Kakuk, T. J.; Cole, S. L.; Zaya, R. M.; Piper, R. C.; Jeffrey, P. Structure-Based Design of HIV Protease Inhibitors: 4-Hydroxycoumarins and 4-Hydroxy-2-Pyrones as Non-peptidic Inhibitors. J. Med. Chem. 1994, 37, 3200-3204. (e) VX-478: Kim, E. E.; Baker, C. T.; Dwyer, M. ID.; Murko, M. A.; Rao, B. G.; Tung, R. D.; Navia, M. R. Crystal Structure of HIV-1 Protease in Complex with VX-478, a Potent and Orally Bioavailable Inhibitor of the Enzyme. J. Am. Chem. Soc. 1995, 117, 1181-1182. (f) ABT-538: Kempf, D. J.; Marsh, K. C.; Denissen, J.; McDonald, E.; Vasavanonda, S.; Flengte, C.; Green, B. E.; Fino, L.; Park, C.; Kong, X.; Wideburg, N. E.; Saldivar, A.; Ruiz, L.; Kati, W. M.; Sham, H. L.; Robins, T.; Stewart, K. D.; Hsu, A.; Plattner, J. J.; Leonard, J. M.; Norbeck, D. W. ABT-538 is a Potent Inhibitor of Human Immunodefi- ciency Virus Protease and has High Oral Bioavailability in Humans. Proc. Natl. Acad. Sci. U.S.A. 1995, 92, 2484-2488.
11. Appelt, K. Crystal Structures of HIV-1 Protease Perspect. Drug Disc. Des. 1993, 1, 23-48.
12. 2 Substituants for HIV-1 Protease Inhibitors. Bioorg. Med. Chem. Lett. 1995, 5, 727-732.
13. (b) Kaldor, S. W.; Dressman, B. A.; Hammond, M.; Appelt, K.; Burgess, J. A.; Lubbehusen, P. P.; Muesing, M. A.; Hatch, S. D.; Wiskerchen, M.; Baxter, A. J. Isophthalic Acid Derivatives: Amino Acid Surrogates for the Inhibition of HIV-1 Protease. Bioorg. Med. Chem. Lett. 1995, 5, 721-726.
14. 3 Spanning Sidechains for the Inhibition of HIV-1 Protease. Bioorg. Med. Chem. Lett. 1995, 5, 715-720.
15. (d) Kaldor, S. W.; Hammond, M.; Dressman, B. A.; Fritz, J. E.; Crowell, T. A.; Hermann, R. A. New Dipeptide Isosteres Useful for the Inhibition of HIV-1 Protease. Bioorg. Med. Chem. Lett. 1994, 4, 1385-1390.
16. (e) Reich, S. H.; Melnick, M.; Davies, J.; Appelt, K.; Lewis, K.; Fuhry, M. M.; Pino, M.; et al. Protein Structure-Based Design of Potent Orally Bioavailable, Nonpeptide Inhibitors of Human Immunodeficiency Virus Protease Proc. Natl. Acad. Sci. U.S.A. 1995 92, 8, 3298.
17. (f) Reich, S. H.; Melnick, M.; Pino, M.; Fuhry, M. M.; Trippe, A.; Appelt, K.; Davies, J. F., II; Wu, B.; Musick, L. Structure-Based Design and Synthesis of Substituted 2-Butanols as Nonpeptidic Inhibitors of HIV Protease: Secondary Amide Series. J. Med. Chem. 1996, 39, 2781-2794.
18. (g) Melnick, M.; Reich, S. H.; Lewis, K. K.; Mitchell, L. J.; Nguyen, D.; Trippe, A. J.; Dawson, H.; Davies, J. F., II; Appelt, K.; Wu, B.; Musick, L.; Gehlhaar, D. K.; Webber, S.; Shetty, B.; Kosa, M.; Andrada, D. Bis Tertiary Amide Inhibitors of the HIV-1 Protease Generated via Protein Structure-Based Iterative Design J. Med. Chem. 1996, 39, 2795-2811.
19. Appelt, K.; Davies, J., Unpublished results.
20. Initial disclosures on AGI343: (a) Shetty, B.; Kaldor, S.; Kalish, V.; Reich, S.; Webber, S. AG1343, An Orally Bioavailable Nonpeptidic HIV-1 Protease Inhibitor. Presented at the 10th International AIDS Conference, Yokohama, Japan, August 1994; paper 321A. (b) Kalish, V.; Kaldor, S.; Shetty, B.; Tatlock, J.; Davies, J.; Hammond, M.; Dressman, B.; Fritz, J.; Appelt, K.; Reich, S.; Musick, L.; Wu, B.; Su, K. Iterative Protein Structure-Based Design and Synthesis of HIV Protease Inhibitors. Proceedings of the XIIIth International Symposium on Medicinal Chemistry, Paris, France, September 1994, p 201s. In early reports, AG1343 was also called LY312857.
21. Initial disclosures on AGI343: (a) Shetty, B.; Kaldor, S.; Kalish, V.; Reich, S.; Webber, S. AG1343, An Orally Bioavailable Nonpeptidic HIV-1 Protease Inhibitor. Presented at the 10th International AIDS Conference, Yokohama, Japan, August 1994; paper 321A. (b) Kalish, V.; Kaldor, S.; Shetty, B.; Tatlock, J.; Davies, J.; Hammond, M.; Dressman, B.; Fritz, J.; Appelt, K.; Reich, S.; Musick, L.; Wu, B.; Su, K. Iterative Protein Structure-Based Design and Synthesis of HIV Protease Inhibitors. Proceedings of the XIIIth International Symposium on Medicinal Chemistry, Paris, France, September 1994, p 201s. In early reports, AG1343 was also called LY312857.
22. Arnold, L. D.; Kalantar, T. H.; Vederas, J. C. Conversion of Serine to Sterochemically Pure β-Substituted α-Amino Acids via β-Lactones. J. Am. Chem. Soc. 1985, 107, 7105-7109.
23. See Parkes, K. E. B.; Bushnell, D. J.; Crackett, P. H.; Dunsdon, S. J.; Freeman, A. C.; Gunn, M. P.; Hopkins, R. A.; Lambert, R. W.; Martin, J. A.; Merrett, J. H.; Redshaw, S.; Spurden, W. C.; Thomas, G. J. Studies Toward the Large-Scale Synthesis of the HIV Proteinase Inhibitor Ro 31-8959. J. Org. Chem. 1994, 59, 3656-3664 and references cited therein.
24. 2 (American Peptide, Santa Clara, CA) as the substrate at pH 5.6: Richards, A. D.; Phylip, L. H.; Farmerie, W. G.; Scarborough, P.; Pavlickova, L.; Kostka, V.; Kay, J. Sensitive, Soluble Chromogenic Substrates for HIV-1 Proteinase. J. Biol. Chem. 1990, 265, 7733-7736.
25. Inhibition constants were determined using the method of Morrison and applying nonlinear curve-fitting methods: Morrison, J. F. Kinetics of the Reversible Inhibition of Enzyme-Catalysed Reactions of Tight-Binding Inhibitors. Biochim. Biophys. Acta 1969, 185, 269-286.
26. 50 of 2-10 nM in this assay.
27. The HIV-1 protease cloning, expression, and purification has been described previously (Hostomsky, Z.; Appelt, K.; Ogden, R. C. Biochem. Biophys. Res. Commun. 1989, 161, 1056-1063).
28. Crystals of the inhibited enzyme were grown by the hanging drop vapor diffusion method from 1.2-1.6 M ammonium sulfate, 5% (vol/vol) dimethyl sulfoxide, 3% (Vol/vol) isopropyl alcohol, and 0.05 M citrate-tartrate buffered at pH = 5.8. The enzyme crystallized in space group P2(1)2(1)2(1) with cell dimensions of a = 52 Å, b = 59 Å, and c = 62 Å. A 2.1 Å X-ray diffraction data set was collected from one crystal using dual area detectors from Area Detector Systems, Inc. Refinement of the AG1343 complex was initiated using the crystal structure of a previously solved inhibited complex as a starting point. Using the X-PLOR program (Brunger, A. T.; Kuriyan, J.; Karplus, M. Science 1987, 235, 458-460),
29. the structure was refined to a crystallographic R-factor of 0.20 using all data between 6 and 2.1 Å. Details of the crystallographic work will be published elsewhere (J. F. Davies and K. Appelt). Atomic coordinates have been deposited in the Protein Data Bank, Chemistry Department, Brookhaven National Laboratories, Long Island, NY 11973. Accession number: 10HR.
30. 50 range of 2-30 nM in the same assays. Details of antiviral and resistance data: Patick, A. K.; Mo, H.; Markowitz, M.; Appelt, K.; Wu, B.; Musick, L.; Kalish, V.; Kaldor, S.; Reich, S.; Ho, D.; Webber, S. Antiviral and Resistance Studies of AG1343, an Orally Bioavailable Inhibitor of Human Immunodeficiency Virus Protease. Antimicrob. Agents Chemother. 1996, 40 (2), 292-297.
31. Animal studies: Pharmacokinetics of AG1343 were determined after intravenous and oral administration of AG1343 to male Sprague-Dawley rats (n = 3), beagle dogs (one male and one female), female cynomolgus monkeys, and marmosets (one male and one female). Intravenous dose of AG1343 ranged from 12.5 to 25 mg/kg, and oral dose of AG1343 ranged from 25 to 50 mg/ kg. AG1343 was delivered as a solution in 5% dextrose to rats, dogs, and monkeys or in propylene glycol:water (50:50) to marmosets. Blood (0.25-2 mL) was sampled from the jugular, femoral, or cephalic vein before dosing and at time points up to 48 h after dosing. Plasma was separated immediately after sampling by centrifugation and stored at -20 °C until analyzed. AG1343 was extracted from plasma and quantified using high performance liquid chromatography (HPLC) and UV detection. Details of preclinical pharmacokinetics will be published in appropriate forum (B. Shetty).
32. Muirhead, G. J.; Williams, P. E. O.; Shaw, T. M.; McClellend, G. R. Investigations of the Effect of Food on the Pharmacokinetics of the HIV Proteinase Inhibitor Ro 31-8959 in Healthy Volunteers. AIDS 1992, 6 (Suppl. l):Abs P74.
33. Initial presentation of these results: Quart, B. D.; Chapman, S. K.; Peterkin, J.; Webber, S.; Oliver, S. Phase I Safety, Tolerance, Pharmacokinetics, and Food Effect Studies of AG1343-A Novel HIV Protease Inhibitor. Proceedings of the 2nd National Conference on Human Retroviruses and Related Infections, Washington, DC, January 1995; Abstract LB3, p 167.