Discovery of potent pyrrolidone-based HIV-1 protease inhibitors with enhanced drug-like properties

Bioorganic and Medicinal Chemistry Letters

Volumn 14, Issue 22, 2004, Pages 5689-5692

  Kazmierski, Wieslaw M ^a   Andrews, Webb ^a   Furfine, Eric ^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; PROTEINASE INHIBITOR;

ANTIVIRAL ACTIVITY; ARTICLE; CHEMICAL REACTION; CONTROLLED STUDY; CRYSTAL STRUCTURE; DRUG POTENCY; DRUG STRUCTURE; DRUG SYNTHESIS; ENZYME INHIBITION; HUMAN IMMUNODEFICIENCY VIRUS 1; MOLECULAR INTERACTION; NONHUMAN; REACTION ANALYSIS; STRUCTURE ACTIVITY RELATION;

DRUG DESIGN; HIV PROTEASE; HIV PROTEASE INHIBITORS; MODELS, MOLECULAR; MOLECULAR CONFORMATION; PYRROLIDINONES; STRUCTURE-ACTIVITY RELATIONSHIP;

HUMAN IMMUNODEFICIENCY VIRUS 1;

EID: 5144222589     PISSN: 0960894X     EISSN: None     Source Type: Journal    
DOI: 10.1016/j.bmcl.2004.08.039     Document Type: Article

References (11)

1. Previous manuscript in this series: Kazmierski, W. M.; Furfine, E.; Gray-Nunez, Y.; Spaltenstein, A.; Wright, L. Bioorg. Med. Chem. Lett. 2004, 14, in press. doi:10.1016/j.bmcl.2004.08.038
2. 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
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. 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
6. Several pairs of analogues in both 1 and 2 series suggested that the trans relationship of P1 and P2 enabled by the pyrrolidone scaffold 2 improves potency approximately by a factor of 20
7. 2 result in overreduction of pyridines to piperidines
8. i = 30 nM), suggesting preference of allyl-P2 over benzyl-P2 in the morpholino series
9. Deprotection of N-, O-acetonide C with TFA gives substantial amounts of the cyclization cleavage products, lacton D and indanolamine E. Additional experimentation allowed us to dramatically suppress the formation of D and E by the use of 4 N HCl in dioxane (95%) and water (5%)
10. 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 26â€"30, 2000, poster MEDI-126
11. We utilized methods described in G. Klopman, S. Wang, and D.M. Balthasar Chem. Inf. Comput. Sci. 32 1992 474 Comparison of relative predicted solubilities for 10, 17b, 19b, and 21 (concentration at saturation 0.526, 0.126, 0.079, and 0.063 μM) indicate that these compounds are predicted to be up to 10-fold more soluble than the reference inhibitor 4 (concentration at saturation 0.0525 μM)