Potent inhibitors of the HIV-1 protease incorporating cyclic urea P1-P2 scaffold

Bioorganic and Medicinal Chemistry Letters

Volumn 14, Issue 22, 2004, Pages 5685-5687

  Kazmierski, Wieslaw M ^a   Furfine, Eric ^a   Gray Nunez, Yolanda ^a   Spaltenstein, Andrew ^a   Wright, Lois ^a  

^a GLAXOSMITHKLINE   (United States)

Author keywords

AIDS; Aspartyl protease inhibitor; HIV 1 protease inhibitor; Peptide mimetic; Peptidomimetic

Indexed keywords

2 PYRROLIDONE DERIVATIVE; ANTIVIRUS AGENT; IMIDAZOLIDINE DERIVATIVE; PROTEINASE INHIBITOR;

ANTIVIRAL ACTIVITY; ARTICLE; CHEMICAL REACTION; CONTROLLED STUDY; DRUG POTENCY; DRUG STRUCTURE; DRUG SYNTHESIS; HUMAN; HUMAN CELL; HUMAN IMMUNODEFICIENCY VIRUS 1; REACTION ANALYSIS; STRUCTURE ACTIVITY RELATION;

CYCLIZATION; DRUG DESIGN; HETEROCYCLIC COMPOUNDS; HIV PROTEASE; HIV PROTEASE INHIBITORS; IMIDAZOLIDINES; MOLECULAR CONFORMATION; STRUCTURE-ACTIVITY RELATIONSHIP; UREA;

HUMAN IMMUNODEFICIENCY VIRUS 1;

EID: 5144223004     PISSN: 0960894X     EISSN: None     Source Type: Journal    
DOI: 10.1016/j.bmcl.2004.08.038     Document Type: Article

References (14)

1. A. Spaltenstein, D. Cleary, B. Bock, W. Kazmierski, E. Furfine, L. Wright, R. Hazen, W. Andrews, M. Almond, R. Tung, and F. Salituro Bioorg. Med. Chem. Lett. 10 2000 1159
2. Kazmierski, W.; Andrews, W.; Baker, C.; Bock, B.; Cleary, D.; Furfine, E.; Gray-Nunez, Y.; Hale, M.; Hazen, R.; Salituro, F.; Schairer, W.; Spaltenstein, A.; Tung, R.; Wright, L. Book of Abstracts, 219th ACS National Meeting, San Francisco, CA, March 26-30, 2000; poster MEDI-126
3. W.M. Kazmierski, E. Furfine, A. Spaltenstein, and L.L. Wright Bioorg. Med. Chem. Lett. 12 2002 3431
4. P.C. Fritch, and W.M. Kazmierski Synthesis 1 1999 112
5. W.M. Kazmierski, and P.C. Fritch Methods in Molecular Medicine 23 (Peptidomimetics Protocols) 1999 281 291
6. W.M. Kazmierski, P. Bevans, E. Furfine, A. Spaltenstein, and H. Yang Bioorg. Med. Chem. Lett. 13 2003 2523
7. Kazmierski, W. M.; Bevans, P.; Furfine, E.; Porter, D.; Spaltenstein, A.; Yang, H. 223rd ACS National Meeting, Orlando, FL, United States, April 7-11, 2002; Poster MEDI-160
8. F.G. Salituro, C.T. Baker, J.J. Court, D.D. Deininger, E.E. Kim, B. Li, P.M. Novak, B.G. Rao, S. Pazhanisamy, M.D. Porter, W.C. Schairer, and R.D. Tung Bioorg. Med. Chem. Lett. 8 1998 3637
9. Kazmierski, W. M.; Andrews, W.; Furfine, E.; Spaltenstein, A.; Wright, L. Bioorg. Med. Chem. Lett. 2004, 14, in press. doi:10.1016/j.bmcl.2004.08.039
10. 13C NMR spectral and mass spectroscopy data for all compounds support the proposed structures
11. D. Askin, K.K. Eng, K. Rossen, R.M. Purick, K.M. Wells, R.P. Volante, and P.J. Reider Tetrahedron Lett. 35 1994 673
12. The deprotection of N-,O-acetonide A with TFA results in substantial amounts of cyclitive cleavage products, lacton B and indanolamine C. Additional experimens revealed that under conditions of 4 N HCl in dioxane (95%) and water (5%) formation of B and C is dramatically suppressed
13. 6-acetone, 400 MHz): δ 8.57 (1H, d, J = 5.3 Hz), 8.42 (1H, s), 8.01 (1H, d, J = 8.0 Hz), 7.80 (1H, m), 7.20 (14H, m), 6.92 (1H, d, J = 8.8 Hz), 5.23 (1H, m), 4.29 (1H, d, J = 16.2 Hz), 4.29 (1H, m), 4.11 (1H, d, J = 16.2 Hz), 3.98 (2H, m), 3.48 (1H, dd), 3.18 (2H, m), 3.00 (4H, m), 2.75 (3H, m), 1.93 (1H, m), 1.88 (1H, m), 1.66 (1H, m)
14. i = 0.05 nM). (a) LHMDS-78°C; (b) MeI; (c) Bn-Br; (d) TFA; (e) Ref. 1; (f) 4 N HCl in dioxane/water (95:5, v/v)