Novel inhibitors of HIV protease: Design, synthesis and biological evaluation of picomolar inhibitors containing cyclic P1/P2 scaffolds

Bioorganic and Medicinal Chemistry Letters

Volumn 10, Issue 11, 2000, Pages 1159-1162

  Spaltenstein, Andrew ^a   Almond, Merrick R ^a,c   Bock, William J ^a,d   Cleary, Darryl G ^a,c   Furfine, Eric S ^a   Hazen, Richard J ^a   Kazmierski, Wieslaw M ^a   Wright, Lois L ^a   Salituro, Francesco G ^b   Tung, Roger D ^b  

^a GLAXOSMITHKLINE   (United States)

^b VERTEX PHARMACEUTICALS   (United States)

^c Division of Organic Chemistry   (United States)

^d Aventis Pharmaceuticals   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

2 IMIDAZOLIDINONE DERIVATIVE; PROTEINASE INHIBITOR; PYRROLIDINE DERIVATIVE;

ANTIVIRAL ACTIVITY; ARTICLE; BLOOD CELL; CELL CULTURE; CHEMICAL MODIFICATION; DRUG DESIGN; DRUG SYNTHESIS; ENZYME INHIBITION; HUMAN; HUMAN CELL; IN VITRO STUDY; STRUCTURE ACTIVITY RELATION;

ANTI-HIV AGENTS; DRUG DESIGN; HIV PROTEASE INHIBITORS; THIAZOLES;

EID: 0034608468     PISSN: 0960894X     EISSN: None     Source Type: Journal    
DOI: 10.1016/S0960-894X(00)00163-3     Document Type: Article

References (26)

1. Morbidity and Mortality Weekly Reports. 48:1999;459.
2. For example see: Opravil, M.; Hirschel, B.; Lazzarin, A.; Furrer, H. J.; Chave, J. P.; Bern, E.; 39th Interscience Conferences on Antimicrobial Agents and Chemotherapy (ICAAC), San Francisco, 1999, Abstract #283.
3. Morbidity and Mortality Weekly Reports. 46:1997;861.
4. (a) Kakuda, T. N.; Strubble, K. A.; Piscitelli, S. C. J. Health-Syst. Pharm. 1998, 55, 233.
5. (b) Hoetelmans
6. (c) R. M. W.; Meehirst, P. L.; Mulder, J. W.; Burger, D. M.; Koks, C. H. W.; Beijnen, J. H. Pharmacy World Sci. 1997, 19, 159.
7. (a) Molla, A.; Richard G. G.; Sun, E.; Kempf, D. J. Antiviral Res. 1998, 39, 1.
8. (b) Furfine, E. S. In Handbook of Experimental Pharmacology; von der Helm, K. Korant, B. (Eds.); in press.
9. Salituro F.G., Baker C.T., Court J.J., Deininger D.D., Kim E.E., Li B., Novak P.M., Rao B.G., Pazhanisamy S., Porter M.D., Schairer W.C., Tung R.D. Bioorg. Med. Chem. Lett. 8:1998;3637.
10. Lin, J. H.; Ostovic, D.; Vacca, J. P. Pharmaceut. Biotechnol. 1998, 11233.
11. Nahm S., Weinreb S.M. Tetrahedron Lett. 22:1981;3815.
12. Thompson W.J., Fitzgerald P.M., Holloway M.K., Emini E.A., Darke P.L., Schwering J.E., Homnick C.F., Nunberg J., Springer J.P., Huff J.R. J. Med. Chem. 35:1992;1685.
13. (a) Cunneen, J. I. J. Chem. Soc. 1947, 134.
14. (b) Pale-Grosdemange, C.; Simon, E. S.; Prime, K. L.; Whitesides, G. M. J. Am. Chem. Soc. 1991, 113, 12.
15. Stewart J.M., Cordts H.P. J. Am. Chem. Soc. 74:1952;5880.
16. Temperature control (0 °C) was found to be important in order to avoid chlorination of the phenyl ring.
17. Castro J.L., Baker R., Guiblin A.R., Hobbs S.C., Jenkins M.R., Russell M.G.N., Beer M.S., Stanton J.A., Scholey K. J. Med. Chem. 37:1994;3023. . We found that the addition of excess triethylamine/DMAP is critical for this transformation. Pyridine alone afforded only trace amounts of the desired product after extended reaction times.
18. Askin D., Eng K.K., Rossen K., Purick R.M., Wells K.M., Volante R.P., Reider P.J. Tetrahedron Lett. 35:1994;673.
19. (a) Schwesinger, R.; Schlemper, H. Angew. Chem. 1987, 99, 1212.
20. (b) Pietzonka, T.; Seebach, D. Chem. Ber. 1991, 124, 1837. P4 phosphazene base is commercially available from Fluka.
21. As evidenced by TLC and NMR analysis of the crude reaction mixtures.
22. Askin D., Eng K.K., Rossen K., Purick R.M., Wells K.M., Volante R.P., Reider P.J. Tetrahedron Lett. 35:1994;673.
23. Vacca J.P., Guare J.P., deSolma S.J., Sanders W.M., Giuliani E.A., Young S.D., Darke P.L., Zugay J., Sigal I.S., Schleif W.A., Quintero J.C., Emini E.A., Andreson P.S., Huff J.R. J. Med. Chem. 34:1991;1225.
24. i for the cis isomer must be at least 10-100-fold greater than that for the trans isomer.
25. Toth M.V., Marshall G.R. Int. J. Pep. Protein Res. 36:1990;544.
26. Daluge S.M., Purifoy D.J.M., Savina P.M., St. Clair M.H., Parry N.R., Dev I.K., Novak P., Ayers K.M., Reardon J.E. Antimicrob. Agents Chemother. 38:1994;1590.