Structure-activity relationships of HIV-1 PR inhibitors containing AHPBA--II. Modification of pyrrolidine ring at P1' proline.

Systematic replacement in the 3- or 4-position of the pyrrolidine ring at P1' proline was carried out. Compound 26, which has a Cl atom in the 4(S)-position was the most active among inhibitors substituted with other halogen atoms or other substituents. Furthermore, the replacement of the Z group in compound 26 with five- or six-membered fused aromatic heterocycle carbonyl groups produced more potent inhibitors. 7-Methoxybenzofuran-2-carbonyl derivative (44) was the best of these and showed Ki = 4.5 nM against HIV PR and IC90S 0.58 microM and 0.06 microM in chronic and acute infections, respectively. These results suggest that the combination of the 4(S)-CI atom and fused bicyclic heterocycles may be effective in improving their cellular penetration.

[1]  H. Handa,et al.  Structure-activity relationships of HIV-1 PR inhibitors containing AHPBA. , 1994, Bioorganic & medicinal chemistry.

[2]  D. Ho,et al.  Quantitation of human immunodeficiency virus type 1 in the blood of infected persons. , 1989, The New England journal of medicine.

[3]  A Wlodawer,et al.  Structure of complex of synthetic HIV-1 protease with a substrate-based inhibitor at 2.3 A resolution. , 1989, Science.

[4]  J. A. Martin,et al.  Recent advances in the design of HIV proteinase inhibitors. , 1992, Antiviral research.

[5]  E. Reddy,et al.  HTLV-III gag protein is processed in yeast cells by the virus pol-protease. , 1986, Science.

[6]  H Enomoto,et al.  Kynostatin (KNI)-227 and -272, highly potent anti-HIV agents: conformationally constrained tripeptide inhibitors of HIV protease containing allophenylnorstatine. , 1992, Chemical & pharmaceutical bulletin.

[7]  M. Karplus,et al.  CHARMM: A program for macromolecular energy, minimization, and dynamics calculations , 1983 .

[8]  W. R. Ewing,et al.  A Short, Stereocontrolled Synthesis of (—)-Detoxinine , 1988 .

[9]  A. Wlodawer,et al.  Structure-based inhibitors of HIV-1 protease. , 1993, Annual review of biochemistry.

[10]  C. Debouck,et al.  The HIV-1 protease as a therapeutic target for AIDS. , 1992, AIDS research and human retroviruses.

[11]  D. Rich,et al.  Pepstatin-derived inhibitors of aspartic proteinases. A close look at an apparent transition-state analogue inhibitor. , 1985, Journal of medicinal chemistry.

[12]  H. Mitsuya,et al.  Molecular targets for AIDS therapy. , 1990, Science.

[13]  G J Williams,et al.  The Protein Data Bank: a computer-based archival file for macromolecular structures. , 1977, Journal of molecular biology.

[14]  N. Yanaihara.  Peptide Chemistry 1992 , 1993 .