Design, synthesis, and evaluation of tetrahydropyrimidinones as an example of a general approach to nonpeptide HIV protease inhibitors

Journal of Medicinal Chemistry

Volumn 40, Issue 11, 1997, Pages 1707-1719

  De Lucca, George V ^a   Liang, Jing ^a   Aldrich, Paul E ^a   Calabrese, Joe ^a   Cordova, Beverly ^a   Klabe, Ronald M ^a   Rayner, Marlene M ^a   Chang, Chong Hwan ^a  

^a DUPONT COMPANY   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

INDINAVIR; PROTEINASE; PROTEINASE INHIBITOR; RITONAVIR; SAQUINAVIR; TETRAHYDROPYRIMIDINONE; UNCLASSIFIED DRUG;

ACQUIRED IMMUNE DEFICIENCY SYNDROME; ARTICLE; CYCLIZATION; DRUG DESIGN; DRUG STRUCTURE; DRUG SYNTHESIS; PREDICTION; PROTEIN CONFORMATION; PROTEINASE INHIBITION; STRUCTURE ACTIVITY RELATION; VIRUS INFECTION; X RAY CRYSTALLOGRAPHY;

BINDING SITES; COMPUTER SIMULATION; CRYSTALLOGRAPHY, X-RAY; CYCLIZATION; DRUG DESIGN; HIV PROTEASE INHIBITORS; HYDROGEN BONDING; MODELS, MOLECULAR; MOLECULAR CONFORMATION; MOLECULAR STRUCTURE; OXIMES; PYRIMIDINONES;

EID: 0031006944     PISSN: 00222623     EISSN: None     Source Type: Journal    
DOI: 10.1021/jm970081i     Document Type: Article

References (59)

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8. For recent reviews, see: (a) Norbeck, D. W.; Kempf, D. J. HIV Protease Inhibitors. Annu. Rep. Med. Chem. 1991, 26, 141-160. (b) Tomasselli, A. G.; Howe, W. J.; Sawyer, T. K.; Wlodawer, A.; Heinrikson, R. L. The Complexities of AIDS: An Assessment of the HIV Protease as a Therapeutic Target. Chimica Oggi 1991, 6-27. (c) Huff, J. R. HIV Protease A Novel Chemotherapeutic Target for AIDS. J. Med. Chem. 1991, 34, 2305-2314. (d) Martin, J. A. Recent Advances in the Design of HIV Proteinase Inhibitors. Antiviral Res. 1992, 17, 265-278. (e) Thaisrivongs, S. HIV Protease Inhibitors. Annu. Rep. Med. Chem. 1994, 29, 133-144. Kempf, D. J. Progress in the Discovery of Orally Bioavailable Inhibitors of HIV Protease. Perspect. Drug Discovery Des. 1994, 2, 427-436. (g) Kempf, D. J. Design of Symmetry-Based, Peptidomimetic Inhibitors of Human Immunodeficiency Virus Protease. Methods Enzymol. 1994, 241, 334-354. (h) Vacca, J. P. Design of Tight-Binding Human Immunodeficiency Virus Type 1 Protease Inhibitors. Methods Enzymol. 1994, 241, 311-334. (i) Wlodawer, A. Rational Drug Design: The Proteinase Inhibitors. Pharmacotherapy 1994, 14, Suppl.), 9S-20S. (j) Erickson, J.; Kempf, D. Structure-Based Design of Symmetric Inhibitors of HIV-1 Protease. Arch. Virol. 1994 (Suppl. 9), 19-29. (k) Darke, P. L.; Huff, J. R. HIV Protease as an Inhibitor Target for the Treatment of AIDS. Adv. Pharmacol. 1995, 25, 399-454. (l) Romines, K. R.; Chrusciel, R. A. 4-Hydroxypyrones and Related Templates as Nonpeptic HIV Protease Inhibitors. Curr. Med. Chem. 1995, 2, 825-838. (m) Gait, M. J.; Kara, J. Progress in Anti-HIV Structure-Based Drug Design. TiBTECH 1995, 13, 430-437. (n) West, M. L.; Fairlie, D. P. Targeting HIV-1 Protease: A Test of Drug-Design Methodologies. TiPS 1995, 16, 67-74. (o) De Clercq, E. Toward Improved Anti-HIV Chemotherapy: Therapeutic Strategies for Intervention With HIV Infections. J. Med. Chem. 1995, 38, 2491-2517. (p) Boehme, R. E.; Borthwick, A. D.; Wyatt, P. G. Antiviral Agents. Annu. Rep. Med. Chem. 1995, 30, 139-149. (q) Chong, K. T. Recent Advances in HIV-1 Protease Inhibitors. Exp. Opin. Invest. Drugs 1996, 5, 115-124. (r) Kempf, D. J.; Sham, H. L. HIV Protease Inhibitors. Curr. Pharm. Des. 1996, 2, 225-246. (s) De Lucca, G. V.; Erickson-Viitanen, S.; Lam, P. Y. S. Cyclic HIV Protease Inhibitors Capable of Displacing the Active Site Structural Water Molecule. Drug Discovery Today 1997, 2, 6-18.
9. For recent reviews, see: (a) Norbeck, D. W.; Kempf, D. J. HIV Protease Inhibitors. Annu. Rep. Med. Chem. 1991, 26, 141-160. (b) Tomasselli, A. G.; Howe, W. J.; Sawyer, T. K.; Wlodawer, A.; Heinrikson, R. L. The Complexities of AIDS: An Assessment of the HIV Protease as a Therapeutic Target. Chimica Oggi 1991, 6-27. (c) Huff, J. R. HIV Protease A Novel Chemotherapeutic Target for AIDS. J. Med. Chem. 1991, 34, 2305-2314. (d) Martin, J. A. Recent Advances in the Design of HIV Proteinase Inhibitors. Antiviral Res. 1992, 17, 265-278. (e) Thaisrivongs, S. HIV Protease Inhibitors. Annu. Rep. Med. Chem. 1994, 29, 133-144. Kempf, D. J. Progress in the Discovery of Orally Bioavailable Inhibitors of HIV Protease. Perspect. Drug Discovery Des. 1994, 2, 427-436. (g) Kempf, D. J. Design of Symmetry-Based, Peptidomimetic Inhibitors of Human Immunodeficiency Virus Protease. Methods Enzymol. 1994, 241, 334-354. (h) Vacca, J. P. Design of Tight-Binding Human Immunodeficiency Virus Type 1 Protease Inhibitors. Methods Enzymol. 1994, 241, 311-334. (i) Wlodawer, A. Rational Drug Design: The Proteinase Inhibitors. Pharmacotherapy 1994, 14, Suppl.), 9S-20S. (j) Erickson, J.; Kempf, D. Structure-Based Design of Symmetric Inhibitors of HIV-1 Protease. Arch. Virol. 1994 (Suppl. 9), 19-29. (k) Darke, P. L.; Huff, J. R. HIV Protease as an Inhibitor Target for the Treatment of AIDS. Adv. Pharmacol. 1995, 25, 399-454. (l) Romines, K. R.; Chrusciel, R. A. 4-Hydroxypyrones and Related Templates as Nonpeptic HIV Protease Inhibitors. Curr. Med. Chem. 1995, 2, 825-838. (m) Gait, M. J.; Kara, J. Progress in Anti-HIV Structure-Based Drug Design. TiBTECH 1995, 13, 430-437. (n) West, M. L.; Fairlie, D. P. Targeting HIV-1 Protease: A Test of Drug-Design Methodologies. TiPS 1995, 16, 67-74. (o) De Clercq, E. Toward Improved Anti-HIV Chemotherapy: Therapeutic Strategies for Intervention With HIV Infections. J. Med. Chem. 1995, 38, 2491-2517. (p) Boehme, R. E.; Borthwick, A. D.; Wyatt, P. G. Antiviral Agents. Annu. Rep. Med. Chem. 1995, 30, 139-149. (q) Chong, K. T. Recent Advances in HIV-1 Protease Inhibitors. Exp. Opin. Invest. Drugs 1996, 5, 115-124. (r) Kempf, D. J.; Sham, H. L. HIV Protease Inhibitors. Curr. Pharm. Des. 1996, 2, 225-246. (s) De Lucca, G. V.; Erickson-Viitanen, S.; Lam, P. Y. S. Cyclic HIV Protease Inhibitors Capable of Displacing the Active Site Structural Water Molecule. Drug Discovery Today 1997, 2, 6-18.
10. For recent reviews, see: (a) Norbeck, D. W.; Kempf, D. J. HIV Protease Inhibitors. Annu. Rep. Med. Chem. 1991, 26, 141-160. (b) Tomasselli, A. G.; Howe, W. J.; Sawyer, T. K.; Wlodawer, A.; Heinrikson, R. L. The Complexities of AIDS: An Assessment of the HIV Protease as a Therapeutic Target. Chimica Oggi 1991, 6-27. (c) Huff, J. R. HIV Protease A Novel Chemotherapeutic Target for AIDS. J. Med. Chem. 1991, 34, 2305-2314. (d) Martin, J. A. Recent Advances in the Design of HIV Proteinase Inhibitors. Antiviral Res. 1992, 17, 265-278. (e) Thaisrivongs, S. HIV Protease Inhibitors. Annu. Rep. Med. Chem. 1994, 29, 133-144. Kempf, D. J. Progress in the Discovery of Orally Bioavailable Inhibitors of HIV Protease. Perspect. Drug Discovery Des. 1994, 2, 427-436. (g) Kempf, D. J. Design of Symmetry-Based, Peptidomimetic Inhibitors of Human Immunodeficiency Virus Protease. Methods Enzymol. 1994, 241, 334-354. (h) Vacca, J. P. Design of Tight-Binding Human Immunodeficiency Virus Type 1 Protease Inhibitors. Methods Enzymol. 1994, 241, 311-334. (i) Wlodawer, A. Rational Drug Design: The Proteinase Inhibitors. Pharmacotherapy 1994, 14, Suppl.), 9S-20S. (j) Erickson, J.; Kempf, D. Structure-Based Design of Symmetric Inhibitors of HIV-1 Protease. Arch. Virol. 1994 (Suppl. 9), 19-29. (k) Darke, P. L.; Huff, J. R. HIV Protease as an Inhibitor Target for the Treatment of AIDS. Adv. Pharmacol. 1995, 25, 399-454. (l) Romines, K. R.; Chrusciel, R. A. 4-Hydroxypyrones and Related Templates as Nonpeptic HIV Protease Inhibitors. Curr. Med. Chem. 1995, 2, 825-838. (m) Gait, M. J.; Kara, J. Progress in Anti-HIV Structure-Based Drug Design. TiBTECH 1995, 13, 430-437. (n) West, M. L.; Fairlie, D. P. Targeting HIV-1 Protease: A Test of Drug-Design Methodologies. TiPS 1995, 16, 67-74. (o) De Clercq, E. Toward Improved Anti-HIV Chemotherapy: Therapeutic Strategies for Intervention With HIV Infections. J. Med. Chem. 1995, 38, 2491-2517. (p) Boehme, R. E.; Borthwick, A. D.; Wyatt, P. G. Antiviral Agents. Annu. Rep. Med. Chem. 1995, 30, 139-149. (q) Chong, K. T. Recent Advances in HIV-1 Protease Inhibitors. Exp. Opin. Invest. Drugs 1996, 5, 115-124. (r) Kempf, D. J.; Sham, H. L. HIV Protease Inhibitors. Curr. Pharm. Des. 1996, 2, 225-246. (s) De Lucca, G. V.; Erickson-Viitanen, S.; Lam, P. Y. S. Cyclic HIV Protease Inhibitors Capable of Displacing the Active Site Structural Water Molecule. Drug Discovery Today 1997, 2, 6-18.
11. For recent reviews, see: (a) Norbeck, D. W.; Kempf, D. J. HIV Protease Inhibitors. Annu. Rep. Med. Chem. 1991, 26, 141-160. (b) Tomasselli, A. G.; Howe, W. J.; Sawyer, T. K.; Wlodawer, A.; Heinrikson, R. L. The Complexities of AIDS: An Assessment of the HIV Protease as a Therapeutic Target. Chimica Oggi 1991, 6-27. (c) Huff, J. R. HIV Protease A Novel Chemotherapeutic Target for AIDS. J. Med. Chem. 1991, 34, 2305-2314. (d) Martin, J. A. Recent Advances in the Design of HIV Proteinase Inhibitors. Antiviral Res. 1992, 17, 265-278. (e) Thaisrivongs, S. HIV Protease Inhibitors. Annu. Rep. Med. Chem. 1994, 29, 133-144. Kempf, D. J. Progress in the Discovery of Orally Bioavailable Inhibitors of HIV Protease. Perspect. Drug Discovery Des. 1994, 2, 427-436. (g) Kempf, D. J. Design of Symmetry-Based, Peptidomimetic Inhibitors of Human Immunodeficiency Virus Protease. Methods Enzymol. 1994, 241, 334-354. (h) Vacca, J. P. Design of Tight-Binding Human Immunodeficiency Virus Type 1 Protease Inhibitors. Methods Enzymol. 1994, 241, 311-334. (i) Wlodawer, A. Rational Drug Design: The Proteinase Inhibitors. Pharmacotherapy 1994, 14, Suppl.), 9S-20S. (j) Erickson, J.; Kempf, D. Structure-Based Design of Symmetric Inhibitors of HIV-1 Protease. Arch. Virol. 1994 (Suppl. 9), 19-29. (k) Darke, P. L.; Huff, J. R. HIV Protease as an Inhibitor Target for the Treatment of AIDS. Adv. Pharmacol. 1995, 25, 399-454. (l) Romines, K. R.; Chrusciel, R. A. 4-Hydroxypyrones and Related Templates as Nonpeptic HIV Protease Inhibitors. Curr. Med. Chem. 1995, 2, 825-838. (m) Gait, M. J.; Kara, J. Progress in Anti-HIV Structure-Based Drug Design. TiBTECH 1995, 13, 430-437. (n) West, M. L.; Fairlie, D. P. Targeting HIV-1 Protease: A Test of Drug-Design Methodologies. TiPS 1995, 16, 67-74. (o) De Clercq, E. Toward Improved Anti-HIV Chemotherapy: Therapeutic Strategies for Intervention With HIV Infections. J. Med. Chem. 1995, 38, 2491-2517. (p) Boehme, R. E.; Borthwick, A. D.; Wyatt, P. G. Antiviral Agents. Annu. Rep. Med. Chem. 1995, 30, 139-149. (q) Chong, K. T. Recent Advances in HIV-1 Protease Inhibitors. Exp. Opin. Invest. Drugs 1996, 5, 115-124. (r) Kempf, D. J.; Sham, H. L. HIV Protease Inhibitors. Curr. Pharm. Des. 1996, 2, 225-246. (s) De Lucca, G. V.; Erickson-Viitanen, S.; Lam, P. Y. S. Cyclic HIV Protease Inhibitors Capable of Displacing the Active Site Structural Water Molecule. Drug Discovery Today 1997, 2, 6-18.
12. For recent reviews, see: (a) Norbeck, D. W.; Kempf, D. J. HIV Protease Inhibitors. Annu. Rep. Med. Chem. 1991, 26, 141-160. (b) Tomasselli, A. G.; Howe, W. J.; Sawyer, T. K.; Wlodawer, A.; Heinrikson, R. L. The Complexities of AIDS: An Assessment of the HIV Protease as a Therapeutic Target. Chimica Oggi 1991, 6-27. (c) Huff, J. R. HIV Protease A Novel Chemotherapeutic Target for AIDS. J. Med. Chem. 1991, 34, 2305-2314. (d) Martin, J. A. Recent Advances in the Design of HIV Proteinase Inhibitors. Antiviral Res. 1992, 17, 265-278. (e) Thaisrivongs, S. HIV Protease Inhibitors. Annu. Rep. Med. Chem. 1994, 29, 133-144. Kempf, D. J. Progress in the Discovery of Orally Bioavailable Inhibitors of HIV Protease. Perspect. Drug Discovery Des. 1994, 2, 427-436. (g) Kempf, D. J. Design of Symmetry-Based, Peptidomimetic Inhibitors of Human Immunodeficiency Virus Protease. Methods Enzymol. 1994, 241, 334-354. (h) Vacca, J. P. Design of Tight-Binding Human Immunodeficiency Virus Type 1 Protease Inhibitors. Methods Enzymol. 1994, 241, 311-334. (i) Wlodawer, A. Rational Drug Design: The Proteinase Inhibitors. Pharmacotherapy 1994, 14, Suppl.), 9S-20S. (j) Erickson, J.; Kempf, D. Structure-Based Design of Symmetric Inhibitors of HIV-1 Protease. Arch. Virol. 1994 (Suppl. 9), 19-29. (k) Darke, P. L.; Huff, J. R. HIV Protease as an Inhibitor Target for the Treatment of AIDS. Adv. Pharmacol. 1995, 25, 399-454. (l) Romines, K. R.; Chrusciel, R. A. 4-Hydroxypyrones and Related Templates as Nonpeptic HIV Protease Inhibitors. Curr. Med. Chem. 1995, 2, 825-838. (m) Gait, M. J.; Kara, J. Progress in Anti-HIV Structure-Based Drug Design. TiBTECH 1995, 13, 430-437. (n) West, M. L.; Fairlie, D. P. Targeting HIV-1 Protease: A Test of Drug-Design Methodologies. TiPS 1995, 16, 67-74. (o) De Clercq, E. Toward Improved Anti-HIV Chemotherapy: Therapeutic Strategies for Intervention With HIV Infections. J. Med. Chem. 1995, 38, 2491-2517. (p) Boehme, R. E.; Borthwick, A. D.; Wyatt, P. G. Antiviral Agents. Annu. Rep. Med. Chem. 1995, 30, 139-149. (q) Chong, K. T. Recent Advances in HIV-1 Protease Inhibitors. Exp. Opin. Invest. Drugs 1996, 5, 115-124. (r) Kempf, D. J.; Sham, H. L. HIV Protease Inhibitors. Curr. Pharm. Des. 1996, 2, 225-246. (s) De Lucca, G. V.; Erickson-Viitanen, S.; Lam, P. Y. S. Cyclic HIV Protease Inhibitors Capable of Displacing the Active Site Structural Water Molecule. Drug Discovery Today 1997, 2, 6-18.
13. For recent reviews, see: (a) Norbeck, D. W.; Kempf, D. J. HIV Protease Inhibitors. Annu. Rep. Med. Chem. 1991, 26, 141-160. (b) Tomasselli, A. G.; Howe, W. J.; Sawyer, T. K.; Wlodawer, A.; Heinrikson, R. L. The Complexities of AIDS: An Assessment of the HIV Protease as a Therapeutic Target. Chimica Oggi 1991, 6-27. (c) Huff, J. R. HIV Protease A Novel Chemotherapeutic Target for AIDS. J. Med. Chem. 1991, 34, 2305-2314. (d) Martin, J. A. Recent Advances in the Design of HIV Proteinase Inhibitors. Antiviral Res. 1992, 17, 265-278. (e) Thaisrivongs, S. HIV Protease Inhibitors. Annu. Rep. Med. Chem. 1994, 29, 133-144. Kempf, D. J. Progress in the Discovery of Orally Bioavailable Inhibitors of HIV Protease. Perspect. Drug Discovery Des. 1994, 2, 427-436. (g) Kempf, D. J. Design of Symmetry-Based, Peptidomimetic Inhibitors of Human Immunodeficiency Virus Protease. Methods Enzymol. 1994, 241, 334-354. (h) Vacca, J. P. Design of Tight-Binding Human Immunodeficiency Virus Type 1 Protease Inhibitors. Methods Enzymol. 1994, 241, 311-334. (i) Wlodawer, A. Rational Drug Design: The Proteinase Inhibitors. Pharmacotherapy 1994, 14, Suppl.), 9S-20S. (j) Erickson, J.; Kempf, D. Structure-Based Design of Symmetric Inhibitors of HIV-1 Protease. Arch. Virol. 1994 (Suppl. 9), 19-29. (k) Darke, P. L.; Huff, J. R. HIV Protease as an Inhibitor Target for the Treatment of AIDS. Adv. Pharmacol. 1995, 25, 399-454. (l) Romines, K. R.; Chrusciel, R. A. 4-Hydroxypyrones and Related Templates as Nonpeptic HIV Protease Inhibitors. Curr. Med. Chem. 1995, 2, 825-838. (m) Gait, M. J.; Kara, J. Progress in Anti-HIV Structure-Based Drug Design. TiBTECH 1995, 13, 430-437. (n) West, M. L.; Fairlie, D. P. Targeting HIV-1 Protease: A Test of Drug-Design Methodologies. TiPS 1995, 16, 67-74. (o) De Clercq, E. Toward Improved Anti-HIV Chemotherapy: Therapeutic Strategies for Intervention With HIV Infections. J. Med. Chem. 1995, 38, 2491-2517. (p) Boehme, R. E.; Borthwick, A. D.; Wyatt, P. G. Antiviral Agents. Annu. Rep. Med. Chem. 1995, 30, 139-149. (q) Chong, K. T. Recent Advances in HIV-1 Protease Inhibitors. Exp. Opin. Invest. Drugs 1996, 5, 115-124. (r) Kempf, D. J.; Sham, H. L. HIV Protease Inhibitors. Curr. Pharm. Des. 1996, 2, 225-246. (s) De Lucca, G. V.; Erickson-Viitanen, S.; Lam, P. Y. S. Cyclic HIV Protease Inhibitors Capable of Displacing the Active Site Structural Water Molecule. Drug Discovery Today 1997, 2, 6-18.
14. For recent reviews, see: (a) Norbeck, D. W.; Kempf, D. J. HIV Protease Inhibitors. Annu. Rep. Med. Chem. 1991, 26, 141-160. (b) Tomasselli, A. G.; Howe, W. J.; Sawyer, T. K.; Wlodawer, A.; Heinrikson, R. L. The Complexities of AIDS: An Assessment of the HIV Protease as a Therapeutic Target. Chimica Oggi 1991, 6-27. (c) Huff, J. R. HIV Protease A Novel Chemotherapeutic Target for AIDS. J. Med. Chem. 1991, 34, 2305-2314. (d) Martin, J. A. Recent Advances in the Design of HIV Proteinase Inhibitors. Antiviral Res. 1992, 17, 265-278. (e) Thaisrivongs, S. HIV Protease Inhibitors. Annu. Rep. Med. Chem. 1994, 29, 133-144. Kempf, D. J. Progress in the Discovery of Orally Bioavailable Inhibitors of HIV Protease. Perspect. Drug Discovery Des. 1994, 2, 427-436. (g) Kempf, D. J. Design of Symmetry-Based, Peptidomimetic Inhibitors of Human Immunodeficiency Virus Protease. Methods Enzymol. 1994, 241, 334-354. (h) Vacca, J. P. Design of Tight-Binding Human Immunodeficiency Virus Type 1 Protease Inhibitors. Methods Enzymol. 1994, 241, 311-334. (i) Wlodawer, A. Rational Drug Design: The Proteinase Inhibitors. Pharmacotherapy 1994, 14, Suppl.), 9S-20S. (j) Erickson, J.; Kempf, D. Structure-Based Design of Symmetric Inhibitors of HIV-1 Protease. Arch. Virol. 1994 (Suppl. 9), 19-29. (k) Darke, P. L.; Huff, J. R. HIV Protease as an Inhibitor Target for the Treatment of AIDS. Adv. Pharmacol. 1995, 25, 399-454. (l) Romines, K. R.; Chrusciel, R. A. 4-Hydroxypyrones and Related Templates as Nonpeptic HIV Protease Inhibitors. Curr. Med. Chem. 1995, 2, 825-838. (m) Gait, M. J.; Kara, J. Progress in Anti-HIV Structure-Based Drug Design. TiBTECH 1995, 13, 430-437. (n) West, M. L.; Fairlie, D. P. Targeting HIV-1 Protease: A Test of Drug-Design Methodologies. TiPS 1995, 16, 67-74. (o) De Clercq, E. Toward Improved Anti-HIV Chemotherapy: Therapeutic Strategies for Intervention With HIV Infections. J. Med. Chem. 1995, 38, 2491-2517. (p) Boehme, R. E.; Borthwick, A. D.; Wyatt, P. G. Antiviral Agents. Annu. Rep. Med. Chem. 1995, 30, 139-149. (q) Chong, K. T. Recent Advances in HIV-1 Protease Inhibitors. Exp. Opin. Invest. Drugs 1996, 5, 115-124. (r) Kempf, D. J.; Sham, H. L. HIV Protease Inhibitors. Curr. Pharm. Des. 1996, 2, 225-246. (s) De Lucca, G. V.; Erickson-Viitanen, S.; Lam, P. Y. S. Cyclic HIV Protease Inhibitors Capable of Displacing the Active Site Structural Water Molecule. Drug Discovery Today 1997, 2, 6-18.
15. For recent reviews, see: (a) Norbeck, D. W.; Kempf, D. J. HIV Protease Inhibitors. Annu. Rep. Med. Chem. 1991, 26, 141-160. (b) Tomasselli, A. G.; Howe, W. J.; Sawyer, T. K.; Wlodawer, A.; Heinrikson, R. L. The Complexities of AIDS: An Assessment of the HIV Protease as a Therapeutic Target. Chimica Oggi 1991, 6-27. (c) Huff, J. R. HIV Protease A Novel Chemotherapeutic Target for AIDS. J. Med. Chem. 1991, 34, 2305-2314. (d) Martin, J. A. Recent Advances in the Design of HIV Proteinase Inhibitors. Antiviral Res. 1992, 17, 265-278. (e) Thaisrivongs, S. HIV Protease Inhibitors. Annu. Rep. Med. Chem. 1994, 29, 133-144. Kempf, D. J. Progress in the Discovery of Orally Bioavailable Inhibitors of HIV Protease. Perspect. Drug Discovery Des. 1994, 2, 427-436. (g) Kempf, D. J. Design of Symmetry-Based, Peptidomimetic Inhibitors of Human Immunodeficiency Virus Protease. Methods Enzymol. 1994, 241, 334-354. (h) Vacca, J. P. Design of Tight-Binding Human Immunodeficiency Virus Type 1 Protease Inhibitors. Methods Enzymol. 1994, 241, 311-334. (i) Wlodawer, A. Rational Drug Design: The Proteinase Inhibitors. Pharmacotherapy 1994, 14, Suppl.), 9S-20S. (j) Erickson, J.; Kempf, D. Structure-Based Design of Symmetric Inhibitors of HIV-1 Protease. Arch. Virol. 1994 (Suppl. 9), 19-29. (k) Darke, P. L.; Huff, J. R. HIV Protease as an Inhibitor Target for the Treatment of AIDS. Adv. Pharmacol. 1995, 25, 399-454. (l) Romines, K. R.; Chrusciel, R. A. 4-Hydroxypyrones and Related Templates as Nonpeptic HIV Protease Inhibitors. Curr. Med. Chem. 1995, 2, 825-838. (m) Gait, M. J.; Kara, J. Progress in Anti-HIV Structure-Based Drug Design. TiBTECH 1995, 13, 430-437. (n) West, M. L.; Fairlie, D. P. Targeting HIV-1 Protease: A Test of Drug-Design Methodologies. TiPS 1995, 16, 67-74. (o) De Clercq, E. Toward Improved Anti-HIV Chemotherapy: Therapeutic Strategies for Intervention With HIV Infections. J. Med. Chem. 1995, 38, 2491-2517. (p) Boehme, R. E.; Borthwick, A. D.; Wyatt, P. G. Antiviral Agents. Annu. Rep. Med. Chem. 1995, 30, 139-149. (q) Chong, K. T. Recent Advances in HIV-1 Protease Inhibitors. Exp. Opin. Invest. Drugs 1996, 5, 115-124. (r) Kempf, D. J.; Sham, H. L. HIV Protease Inhibitors. Curr. Pharm. Des. 1996, 2, 225-246. (s) De Lucca, G. V.; Erickson-Viitanen, S.; Lam, P. Y. S. Cyclic HIV Protease Inhibitors Capable of Displacing the Active Site Structural Water Molecule. Drug Discovery Today 1997, 2, 6-18.
16. For recent reviews, see: (a) Norbeck, D. W.; Kempf, D. J. HIV Protease Inhibitors. Annu. Rep. Med. Chem. 1991, 26, 141-160. (b) Tomasselli, A. G.; Howe, W. J.; Sawyer, T. K.; Wlodawer, A.; Heinrikson, R. L. The Complexities of AIDS: An Assessment of the HIV Protease as a Therapeutic Target. Chimica Oggi 1991, 6-27. (c) Huff, J. R. HIV Protease A Novel Chemotherapeutic Target for AIDS. J. Med. Chem. 1991, 34, 2305-2314. (d) Martin, J. A. Recent Advances in the Design of HIV Proteinase Inhibitors. Antiviral Res. 1992, 17, 265-278. (e) Thaisrivongs, S. HIV Protease Inhibitors. Annu. Rep. Med. Chem. 1994, 29, 133-144. Kempf, D. J. Progress in the Discovery of Orally Bioavailable Inhibitors of HIV Protease. Perspect. Drug Discovery Des. 1994, 2, 427-436. (g) Kempf, D. J. Design of Symmetry-Based, Peptidomimetic Inhibitors of Human Immunodeficiency Virus Protease. Methods Enzymol. 1994, 241, 334-354. (h) Vacca, J. P. Design of Tight-Binding Human Immunodeficiency Virus Type 1 Protease Inhibitors. Methods Enzymol. 1994, 241, 311-334. (i) Wlodawer, A. Rational Drug Design: The Proteinase Inhibitors. Pharmacotherapy 1994, 14, Suppl.), 9S-20S. (j) Erickson, J.; Kempf, D. Structure-Based Design of Symmetric Inhibitors of HIV-1 Protease. Arch. Virol. 1994 (Suppl. 9), 19-29. (k) Darke, P. L.; Huff, J. R. HIV Protease as an Inhibitor Target for the Treatment of AIDS. Adv. Pharmacol. 1995, 25, 399-454. (l) Romines, K. R.; Chrusciel, R. A. 4-Hydroxypyrones and Related Templates as Nonpeptic HIV Protease Inhibitors. Curr. Med. Chem. 1995, 2, 825-838. (m) Gait, M. J.; Kara, J. Progress in Anti-HIV Structure-Based Drug Design. TiBTECH 1995, 13, 430-437. (n) West, M. L.; Fairlie, D. P. Targeting HIV-1 Protease: A Test of Drug-Design Methodologies. TiPS 1995, 16, 67-74. (o) De Clercq, E. Toward Improved Anti-HIV Chemotherapy: Therapeutic Strategies for Intervention With HIV Infections. J. Med. Chem. 1995, 38, 2491-2517. (p) Boehme, R. E.; Borthwick, A. D.; Wyatt, P. G. Antiviral Agents. Annu. Rep. Med. Chem. 1995, 30, 139-149. (q) Chong, K. T. Recent Advances in HIV-1 Protease Inhibitors. Exp. Opin. Invest. Drugs 1996, 5, 115-124. (r) Kempf, D. J.; Sham, H. L. HIV Protease Inhibitors. Curr. Pharm. Des. 1996, 2, 225-246. (s) De Lucca, G. V.; Erickson-Viitanen, S.; Lam, P. Y. S. Cyclic HIV Protease Inhibitors Capable of Displacing the Active Site Structural Water Molecule. Drug Discovery Today 1997, 2, 6-18.
17. For recent reviews, see: (a) Norbeck, D. W.; Kempf, D. J. HIV Protease Inhibitors. Annu. Rep. Med. Chem. 1991, 26, 141-160. (b) Tomasselli, A. G.; Howe, W. J.; Sawyer, T. K.; Wlodawer, A.; Heinrikson, R. L. The Complexities of AIDS: An Assessment of the HIV Protease as a Therapeutic Target. Chimica Oggi 1991, 6-27. (c) Huff, J. R. HIV Protease A Novel Chemotherapeutic Target for AIDS. J. Med. Chem. 1991, 34, 2305-2314. (d) Martin, J. A. Recent Advances in the Design of HIV Proteinase Inhibitors. Antiviral Res. 1992, 17, 265-278. (e) Thaisrivongs, S. HIV Protease Inhibitors. Annu. Rep. Med. Chem. 1994, 29, 133-144. Kempf, D. J. Progress in the Discovery of Orally Bioavailable Inhibitors of HIV Protease. Perspect. Drug Discovery Des. 1994, 2, 427-436. (g) Kempf, D. J. Design of Symmetry-Based, Peptidomimetic Inhibitors of Human Immunodeficiency Virus Protease. Methods Enzymol. 1994, 241, 334-354. (h) Vacca, J. P. Design of Tight-Binding Human Immunodeficiency Virus Type 1 Protease Inhibitors. Methods Enzymol. 1994, 241, 311-334. (i) Wlodawer, A. Rational Drug Design: The Proteinase Inhibitors. Pharmacotherapy 1994, 14, Suppl.), 9S-20S. (j) Erickson, J.; Kempf, D. Structure-Based Design of Symmetric Inhibitors of HIV-1 Protease. Arch. Virol. 1994 (Suppl. 9), 19-29. (k) Darke, P. L.; Huff, J. R. HIV Protease as an Inhibitor Target for the Treatment of AIDS. Adv. Pharmacol. 1995, 25, 399-454. (l) Romines, K. R.; Chrusciel, R. A. 4-Hydroxypyrones and Related Templates as Nonpeptic HIV Protease Inhibitors. Curr. Med. Chem. 1995, 2, 825-838. (m) Gait, M. J.; Kara, J. Progress in Anti-HIV Structure-Based Drug Design. TiBTECH 1995, 13, 430-437. (n) West, M. L.; Fairlie, D. P. Targeting HIV-1 Protease: A Test of Drug-Design Methodologies. TiPS 1995, 16, 67-74. (o) De Clercq, E. Toward Improved Anti-HIV Chemotherapy: Therapeutic Strategies for Intervention With HIV Infections. J. Med. Chem. 1995, 38, 2491-2517. (p) Boehme, R. E.; Borthwick, A. D.; Wyatt, P. G. Antiviral Agents. Annu. Rep. Med. Chem. 1995, 30, 139-149. (q) Chong, K. T. Recent Advances in HIV-1 Protease Inhibitors. Exp. Opin. Invest. Drugs 1996, 5, 115-124. (r) Kempf, D. J.; Sham, H. L. HIV Protease Inhibitors. Curr. Pharm. Des. 1996, 2, 225-246. (s) De Lucca, G. V.; Erickson-Viitanen, S.; Lam, P. Y. S. Cyclic HIV Protease Inhibitors Capable of Displacing the Active Site Structural Water Molecule. Drug Discovery Today 1997, 2, 6-18.
18. For recent reviews, see: (a) Norbeck, D. W.; Kempf, D. J. HIV Protease Inhibitors. Annu. Rep. Med. Chem. 1991, 26, 141-160. (b) Tomasselli, A. G.; Howe, W. J.; Sawyer, T. K.; Wlodawer, A.; Heinrikson, R. L. The Complexities of AIDS: An Assessment of the HIV Protease as a Therapeutic Target. Chimica Oggi 1991, 6-27. (c) Huff, J. R. HIV Protease A Novel Chemotherapeutic Target for AIDS. J. Med. Chem. 1991, 34, 2305-2314. (d) Martin, J. A. Recent Advances in the Design of HIV Proteinase Inhibitors. Antiviral Res. 1992, 17, 265-278. (e) Thaisrivongs, S. HIV Protease Inhibitors. Annu. Rep. Med. Chem. 1994, 29, 133-144. Kempf, D. J. Progress in the Discovery of Orally Bioavailable Inhibitors of HIV Protease. Perspect. Drug Discovery Des. 1994, 2, 427-436. (g) Kempf, D. J. Design of Symmetry-Based, Peptidomimetic Inhibitors of Human Immunodeficiency Virus Protease. Methods Enzymol. 1994, 241, 334-354. (h) Vacca, J. P. Design of Tight-Binding Human Immunodeficiency Virus Type 1 Protease Inhibitors. Methods Enzymol. 1994, 241, 311-334. (i) Wlodawer, A. Rational Drug Design: The Proteinase Inhibitors. Pharmacotherapy 1994, 14, Suppl.), 9S-20S. (j) Erickson, J.; Kempf, D. Structure-Based Design of Symmetric Inhibitors of HIV-1 Protease. Arch. Virol. 1994 (Suppl. 9), 19-29. (k) Darke, P. L.; Huff, J. R. HIV Protease as an Inhibitor Target for the Treatment of AIDS. Adv. Pharmacol. 1995, 25, 399-454. (l) Romines, K. R.; Chrusciel, R. A. 4-Hydroxypyrones and Related Templates as Nonpeptic HIV Protease Inhibitors. Curr. Med. Chem. 1995, 2, 825-838. (m) Gait, M. J.; Kara, J. Progress in Anti-HIV Structure-Based Drug Design. TiBTECH 1995, 13, 430-437. (n) West, M. L.; Fairlie, D. P. Targeting HIV-1 Protease: A Test of Drug-Design Methodologies. TiPS 1995, 16, 67-74. (o) De Clercq, E. Toward Improved Anti-HIV Chemotherapy: Therapeutic Strategies for Intervention With HIV Infections. J. Med. Chem. 1995, 38, 2491-2517. (p) Boehme, R. E.; Borthwick, A. D.; Wyatt, P. G. Antiviral Agents. Annu. Rep. Med. Chem. 1995, 30, 139-149. (q) Chong, K. T. Recent Advances in HIV-1 Protease Inhibitors. Exp. Opin. Invest. Drugs 1996, 5, 115-124. (r) Kempf, D. J.; Sham, H. L. HIV Protease Inhibitors. Curr. Pharm. Des. 1996, 2, 225-246. (s) De Lucca, G. V.; Erickson-Viitanen, S.; Lam, P. Y. S. Cyclic HIV Protease Inhibitors Capable of Displacing the Active Site Structural Water Molecule. Drug Discovery Today 1997, 2, 6-18.
19. For recent reviews, see: (a) Norbeck, D. W.; Kempf, D. J. HIV Protease Inhibitors. Annu. Rep. Med. Chem. 1991, 26, 141-160. (b) Tomasselli, A. G.; Howe, W. J.; Sawyer, T. K.; Wlodawer, A.; Heinrikson, R. L. The Complexities of AIDS: An Assessment of the HIV Protease as a Therapeutic Target. Chimica Oggi 1991, 6-27. (c) Huff, J. R. HIV Protease A Novel Chemotherapeutic Target for AIDS. J. Med. Chem. 1991, 34, 2305-2314. (d) Martin, J. A. Recent Advances in the Design of HIV Proteinase Inhibitors. Antiviral Res. 1992, 17, 265-278. (e) Thaisrivongs, S. HIV Protease Inhibitors. Annu. Rep. Med. Chem. 1994, 29, 133-144. Kempf, D. J. Progress in the Discovery of Orally Bioavailable Inhibitors of HIV Protease. Perspect. Drug Discovery Des. 1994, 2, 427-436. (g) Kempf, D. J. Design of Symmetry-Based, Peptidomimetic Inhibitors of Human Immunodeficiency Virus Protease. Methods Enzymol. 1994, 241, 334-354. (h) Vacca, J. P. Design of Tight-Binding Human Immunodeficiency Virus Type 1 Protease Inhibitors. Methods Enzymol. 1994, 241, 311-334. (i) Wlodawer, A. Rational Drug Design: The Proteinase Inhibitors. Pharmacotherapy 1994, 14, Suppl.), 9S-20S. (j) Erickson, J.; Kempf, D. Structure-Based Design of Symmetric Inhibitors of HIV-1 Protease. Arch. Virol. 1994 (Suppl. 9), 19-29. (k) Darke, P. L.; Huff, J. R. HIV Protease as an Inhibitor Target for the Treatment of AIDS. Adv. Pharmacol. 1995, 25, 399-454. (l) Romines, K. R.; Chrusciel, R. A. 4-Hydroxypyrones and Related Templates as Nonpeptic HIV Protease Inhibitors. Curr. Med. Chem. 1995, 2, 825-838. (m) Gait, M. J.; Kara, J. Progress in Anti-HIV Structure-Based Drug Design. TiBTECH 1995, 13, 430-437. (n) West, M. L.; Fairlie, D. P. Targeting HIV-1 Protease: A Test of Drug-Design Methodologies. TiPS 1995, 16, 67-74. (o) De Clercq, E. Toward Improved Anti-HIV Chemotherapy: Therapeutic Strategies for Intervention With HIV Infections. J. Med. Chem. 1995, 38, 2491-2517. (p) Boehme, R. E.; Borthwick, A. D.; Wyatt, P. G. Antiviral Agents. Annu. Rep. Med. Chem. 1995, 30, 139-149. (q) Chong, K. T. Recent Advances in HIV-1 Protease Inhibitors. Exp. Opin. Invest. Drugs 1996, 5, 115-124. (r) Kempf, D. J.; Sham, H. L. HIV Protease Inhibitors. Curr. Pharm. Des. 1996, 2, 225-246. (s) De Lucca, G. V.; Erickson-Viitanen, S.; Lam, P. Y. S. Cyclic HIV Protease Inhibitors Capable of Displacing the Active Site Structural Water Molecule. Drug Discovery Today 1997, 2, 6-18.
20. For recent reviews, see: (a) Norbeck, D. W.; Kempf, D. J. HIV Protease Inhibitors. Annu. Rep. Med. Chem. 1991, 26, 141-160. (b) Tomasselli, A. G.; Howe, W. J.; Sawyer, T. K.; Wlodawer, A.; Heinrikson, R. L. The Complexities of AIDS: An Assessment of the HIV Protease as a Therapeutic Target. Chimica Oggi 1991, 6-27. (c) Huff, J. R. HIV Protease A Novel Chemotherapeutic Target for AIDS. J. Med. Chem. 1991, 34, 2305-2314. (d) Martin, J. A. Recent Advances in the Design of HIV Proteinase Inhibitors. Antiviral Res. 1992, 17, 265-278. (e) Thaisrivongs, S. HIV Protease Inhibitors. Annu. Rep. Med. Chem. 1994, 29, 133-144. Kempf, D. J. Progress in the Discovery of Orally Bioavailable Inhibitors of HIV Protease. Perspect. Drug Discovery Des. 1994, 2, 427-436. (g) Kempf, D. J. Design of Symmetry-Based, Peptidomimetic Inhibitors of Human Immunodeficiency Virus Protease. Methods Enzymol. 1994, 241, 334-354. (h) Vacca, J. P. Design of Tight-Binding Human Immunodeficiency Virus Type 1 Protease Inhibitors. Methods Enzymol. 1994, 241, 311-334. (i) Wlodawer, A. Rational Drug Design: The Proteinase Inhibitors. Pharmacotherapy 1994, 14, Suppl.), 9S-20S. (j) Erickson, J.; Kempf, D. Structure-Based Design of Symmetric Inhibitors of HIV-1 Protease. Arch. Virol. 1994 (Suppl. 9), 19-29. (k) Darke, P. L.; Huff, J. R. HIV Protease as an Inhibitor Target for the Treatment of AIDS. Adv. Pharmacol. 1995, 25, 399-454. (l) Romines, K. R.; Chrusciel, R. A. 4-Hydroxypyrones and Related Templates as Nonpeptic HIV Protease Inhibitors. Curr. Med. Chem. 1995, 2, 825-838. (m) Gait, M. J.; Kara, J. Progress in Anti-HIV Structure-Based Drug Design. TiBTECH 1995, 13, 430-437. (n) West, M. L.; Fairlie, D. P. Targeting HIV-1 Protease: A Test of Drug-Design Methodologies. TiPS 1995, 16, 67-74. (o) De Clercq, E. Toward Improved Anti-HIV Chemotherapy: Therapeutic Strategies for Intervention With HIV Infections. J. Med. Chem. 1995, 38, 2491-2517. (p) Boehme, R. E.; Borthwick, A. D.; Wyatt, P. G. Antiviral Agents. Annu. Rep. Med. Chem. 1995, 30, 139-149. (q) Chong, K. T. Recent Advances in HIV-1 Protease Inhibitors. Exp. Opin. Invest. Drugs 1996, 5, 115-124. (r) Kempf, D. J.; Sham, H. L. HIV Protease Inhibitors. Curr. Pharm. Des. 1996, 2, 225-246. (s) De Lucca, G. V.; Erickson-Viitanen, S.; Lam, P. Y. S. Cyclic HIV Protease Inhibitors Capable of Displacing the Active Site Structural Water Molecule. Drug Discovery Today 1997, 2, 6-18.
21. For recent reviews, see: (a) Norbeck, D. W.; Kempf, D. J. HIV Protease Inhibitors. Annu. Rep. Med. Chem. 1991, 26, 141-160. (b) Tomasselli, A. G.; Howe, W. J.; Sawyer, T. K.; Wlodawer, A.; Heinrikson, R. L. The Complexities of AIDS: An Assessment of the HIV Protease as a Therapeutic Target. Chimica Oggi 1991, 6-27. (c) Huff, J. R. HIV Protease A Novel Chemotherapeutic Target for AIDS. J. Med. Chem. 1991, 34, 2305-2314. (d) Martin, J. A. Recent Advances in the Design of HIV Proteinase Inhibitors. Antiviral Res. 1992, 17, 265-278. (e) Thaisrivongs, S. HIV Protease Inhibitors. Annu. Rep. Med. Chem. 1994, 29, 133-144. Kempf, D. J. Progress in the Discovery of Orally Bioavailable Inhibitors of HIV Protease. Perspect. Drug Discovery Des. 1994, 2, 427-436. (g) Kempf, D. J. Design of Symmetry-Based, Peptidomimetic Inhibitors of Human Immunodeficiency Virus Protease. Methods Enzymol. 1994, 241, 334-354. (h) Vacca, J. P. Design of Tight-Binding Human Immunodeficiency Virus Type 1 Protease Inhibitors. Methods Enzymol. 1994, 241, 311-334. (i) Wlodawer, A. Rational Drug Design: The Proteinase Inhibitors. Pharmacotherapy 1994, 14, Suppl.), 9S-20S. (j) Erickson, J.; Kempf, D. Structure-Based Design of Symmetric Inhibitors of HIV-1 Protease. Arch. Virol. 1994 (Suppl. 9), 19-29. (k) Darke, P. L.; Huff, J. R. HIV Protease as an Inhibitor Target for the Treatment of AIDS. Adv. Pharmacol. 1995, 25, 399-454. (l) Romines, K. R.; Chrusciel, R. A. 4-Hydroxypyrones and Related Templates as Nonpeptic HIV Protease Inhibitors. Curr. Med. Chem. 1995, 2, 825-838. (m) Gait, M. J.; Kara, J. Progress in Anti-HIV Structure-Based Drug Design. TiBTECH 1995, 13, 430-437. (n) West, M. L.; Fairlie, D. P. Targeting HIV-1 Protease: A Test of Drug-Design Methodologies. TiPS 1995, 16, 67-74. (o) De Clercq, E. Toward Improved Anti-HIV Chemotherapy: Therapeutic Strategies for Intervention With HIV Infections. J. Med. Chem. 1995, 38, 2491-2517. (p) Boehme, R. E.; Borthwick, A. D.; Wyatt, P. G. Antiviral Agents. Annu. Rep. Med. Chem. 1995, 30, 139-149. (q) Chong, K. T. Recent Advances in HIV-1 Protease Inhibitors. Exp. Opin. Invest. Drugs 1996, 5, 115-124. (r) Kempf, D. J.; Sham, H. L. HIV Protease Inhibitors. Curr. Pharm. Des. 1996, 2, 225-246. (s) De Lucca, G. V.; Erickson-Viitanen, S.; Lam, P. Y. S. Cyclic HIV Protease Inhibitors Capable of Displacing the Active Site Structural Water Molecule. Drug Discovery Today 1997, 2, 6-18.
22. For recent reviews, see: (a) Norbeck, D. W.; Kempf, D. J. HIV Protease Inhibitors. Annu. Rep. Med. Chem. 1991, 26, 141-160. (b) Tomasselli, A. G.; Howe, W. J.; Sawyer, T. K.; Wlodawer, A.; Heinrikson, R. L. The Complexities of AIDS: An Assessment of the HIV Protease as a Therapeutic Target. Chimica Oggi 1991, 6-27. (c) Huff, J. R. HIV Protease A Novel Chemotherapeutic Target for AIDS. J. Med. Chem. 1991, 34, 2305-2314. (d) Martin, J. A. Recent Advances in the Design of HIV Proteinase Inhibitors. Antiviral Res. 1992, 17, 265-278. (e) Thaisrivongs, S. HIV Protease Inhibitors. Annu. Rep. Med. Chem. 1994, 29, 133-144. Kempf, D. J. Progress in the Discovery of Orally Bioavailable Inhibitors of HIV Protease. Perspect. Drug Discovery Des. 1994, 2, 427-436. (g) Kempf, D. J. Design of Symmetry-Based, Peptidomimetic Inhibitors of Human Immunodeficiency Virus Protease. Methods Enzymol. 1994, 241, 334-354. (h) Vacca, J. P. Design of Tight-Binding Human Immunodeficiency Virus Type 1 Protease Inhibitors. Methods Enzymol. 1994, 241, 311-334. (i) Wlodawer, A. Rational Drug Design: The Proteinase Inhibitors. Pharmacotherapy 1994, 14, Suppl.), 9S-20S. (j) Erickson, J.; Kempf, D. Structure-Based Design of Symmetric Inhibitors of HIV-1 Protease. Arch. Virol. 1994 (Suppl. 9), 19-29. (k) Darke, P. L.; Huff, J. R. HIV Protease as an Inhibitor Target for the Treatment of AIDS. Adv. Pharmacol. 1995, 25, 399-454. (l) Romines, K. R.; Chrusciel, R. A. 4-Hydroxypyrones and Related Templates as Nonpeptic HIV Protease Inhibitors. Curr. Med. Chem. 1995, 2, 825-838. (m) Gait, M. J.; Kara, J. Progress in Anti-HIV Structure-Based Drug Design. TiBTECH 1995, 13, 430-437. (n) West, M. L.; Fairlie, D. P. Targeting HIV-1 Protease: A Test of Drug-Design Methodologies. TiPS 1995, 16, 67-74. (o) De Clercq, E. Toward Improved Anti-HIV Chemotherapy: Therapeutic Strategies for Intervention With HIV Infections. J. Med. Chem. 1995, 38, 2491-2517. (p) Boehme, R. E.; Borthwick, A. D.; Wyatt, P. G. Antiviral Agents. Annu. Rep. Med. Chem. 1995, 30, 139-149. (q) Chong, K. T. Recent Advances in HIV-1 Protease Inhibitors. Exp. Opin. Invest. Drugs 1996, 5, 115-124. (r) Kempf, D. J.; Sham, H. L. HIV Protease Inhibitors. Curr. Pharm. Des. 1996, 2, 225-246. (s) De Lucca, G. V.; Erickson-Viitanen, S.; Lam, P. Y. S. Cyclic HIV Protease Inhibitors Capable of Displacing the Active Site Structural Water Molecule. Drug Discovery Today 1997, 2, 6-18.
23. For recent reviews, see: (a) Norbeck, D. W.; Kempf, D. J. HIV Protease Inhibitors. Annu. Rep. Med. Chem. 1991, 26, 141-160. (b) Tomasselli, A. G.; Howe, W. J.; Sawyer, T. K.; Wlodawer, A.; Heinrikson, R. L. The Complexities of AIDS: An Assessment of the HIV Protease as a Therapeutic Target. Chimica Oggi 1991, 6-27. (c) Huff, J. R. HIV Protease A Novel Chemotherapeutic Target for AIDS. J. Med. Chem. 1991, 34, 2305-2314. (d) Martin, J. A. Recent Advances in the Design of HIV Proteinase Inhibitors. Antiviral Res. 1992, 17, 265-278. (e) Thaisrivongs, S. HIV Protease Inhibitors. Annu. Rep. Med. Chem. 1994, 29, 133-144. Kempf, D. J. Progress in the Discovery of Orally Bioavailable Inhibitors of HIV Protease. Perspect. Drug Discovery Des. 1994, 2, 427-436. (g) Kempf, D. J. Design of Symmetry-Based, Peptidomimetic Inhibitors of Human Immunodeficiency Virus Protease. Methods Enzymol. 1994, 241, 334-354. (h) Vacca, J. P. Design of Tight-Binding Human Immunodeficiency Virus Type 1 Protease Inhibitors. Methods Enzymol. 1994, 241, 311-334. (i) Wlodawer, A. Rational Drug Design: The Proteinase Inhibitors. Pharmacotherapy 1994, 14, Suppl.), 9S-20S. (j) Erickson, J.; Kempf, D. Structure-Based Design of Symmetric Inhibitors of HIV-1 Protease. Arch. Virol. 1994 (Suppl. 9), 19-29. (k) Darke, P. L.; Huff, J. R. HIV Protease as an Inhibitor Target for the Treatment of AIDS. Adv. Pharmacol. 1995, 25, 399-454. (l) Romines, K. R.; Chrusciel, R. A. 4-Hydroxypyrones and Related Templates as Nonpeptic HIV Protease Inhibitors. Curr. Med. Chem. 1995, 2, 825-838. (m) Gait, M. J.; Kara, J. Progress in Anti-HIV Structure-Based Drug Design. TiBTECH 1995, 13, 430-437. (n) West, M. L.; Fairlie, D. P. Targeting HIV-1 Protease: A Test of Drug-Design Methodologies. TiPS 1995, 16, 67-74. (o) De Clercq, E. Toward Improved Anti-HIV Chemotherapy: Therapeutic Strategies for Intervention With HIV Infections. J. Med. Chem. 1995, 38, 2491-2517. (p) Boehme, R. E.; Borthwick, A. D.; Wyatt, P. G. Antiviral Agents. Annu. Rep. Med. Chem. 1995, 30, 139-149. (q) Chong, K. T. Recent Advances in HIV-1 Protease Inhibitors. Exp. Opin. Invest. Drugs 1996, 5, 115-124. (r) Kempf, D. J.; Sham, H. L. HIV Protease Inhibitors. Curr. Pharm. Des. 1996, 2, 225-246. (s) De Lucca, G. V.; Erickson-Viitanen, S.; Lam, P. Y. S. Cyclic HIV Protease Inhibitors Capable of Displacing the Active Site Structural Water Molecule. Drug Discovery Today 1997, 2, 6-18.
24. For recent reviews, see: (a) Norbeck, D. W.; Kempf, D. J. HIV Protease Inhibitors. Annu. Rep. Med. Chem. 1991, 26, 141-160. (b) Tomasselli, A. G.; Howe, W. J.; Sawyer, T. K.; Wlodawer, A.; Heinrikson, R. L. The Complexities of AIDS: An Assessment of the HIV Protease as a Therapeutic Target. Chimica Oggi 1991, 6-27. (c) Huff, J. R. HIV Protease A Novel Chemotherapeutic Target for AIDS. J. Med. Chem. 1991, 34, 2305-2314. (d) Martin, J. A. Recent Advances in the Design of HIV Proteinase Inhibitors. Antiviral Res. 1992, 17, 265-278. (e) Thaisrivongs, S. HIV Protease Inhibitors. Annu. Rep. Med. Chem. 1994, 29, 133-144. Kempf, D. J. Progress in the Discovery of Orally Bioavailable Inhibitors of HIV Protease. Perspect. Drug Discovery Des. 1994, 2, 427-436. (g) Kempf, D. J. Design of Symmetry-Based, Peptidomimetic Inhibitors of Human Immunodeficiency Virus Protease. Methods Enzymol. 1994, 241, 334-354. (h) Vacca, J. P. Design of Tight-Binding Human Immunodeficiency Virus Type 1 Protease Inhibitors. Methods Enzymol. 1994, 241, 311-334. (i) Wlodawer, A. Rational Drug Design: The Proteinase Inhibitors. Pharmacotherapy 1994, 14, Suppl.), 9S-20S. (j) Erickson, J.; Kempf, D. Structure-Based Design of Symmetric Inhibitors of HIV-1 Protease. Arch. Virol. 1994 (Suppl. 9), 19-29. (k) Darke, P. L.; Huff, J. R. HIV Protease as an Inhibitor Target for the Treatment of AIDS. Adv. Pharmacol. 1995, 25, 399-454. (l) Romines, K. R.; Chrusciel, R. A. 4-Hydroxypyrones and Related Templates as Nonpeptic HIV Protease Inhibitors. Curr. Med. Chem. 1995, 2, 825-838. (m) Gait, M. J.; Kara, J. Progress in Anti-HIV Structure-Based Drug Design. TiBTECH 1995, 13, 430-437. (n) West, M. L.; Fairlie, D. P. Targeting HIV-1 Protease: A Test of Drug-Design Methodologies. TiPS 1995, 16, 67-74. (o) De Clercq, E. Toward Improved Anti-HIV Chemotherapy: Therapeutic Strategies for Intervention With HIV Infections. J. Med. Chem. 1995, 38, 2491-2517. (p) Boehme, R. E.; Borthwick, A. D.; Wyatt, P. G. Antiviral Agents. Annu. Rep. Med. Chem. 1995, 30, 139-149. (q) Chong, K. T. Recent Advances in HIV-1 Protease Inhibitors. Exp. Opin. Invest. Drugs 1996, 5, 115-124. (r) Kempf, D. J.; Sham, H. L. HIV Protease Inhibitors. Curr. Pharm. Des. 1996, 2, 225-246. (s) De Lucca, G. V.; Erickson-Viitanen, S.; Lam, P. Y. S. Cyclic HIV Protease Inhibitors Capable of Displacing the Active Site Structural Water Molecule. Drug Discovery Today 1997, 2, 6-18.
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47. 11b
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