Abstract

The principal goal of this research is the design and synthesis of structurally diverse, orally bioavailable HIV-1 protease inhibitors based on 3,5- and 2,5-linked pyrrolinones. Related objectives include: (i) further elucidation of the solution and solid-state conformations of the pyrrolinones; (ii) generalization of the synthetic protocols to accommodate side-chains of both coded and uncoded amino acids; (iii) development of solid-phase syntheses to facilitate library construction; and (iv) inhibition of other biomedically important proteases, demonstrating that the chosen scaffolds are useful platforms.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI042010-02
Application #
2673133
Study Section
AIDS and Related Research Study Section 4 (ARRD)
Project Start
1997-07-01
Project End
2000-06-30
Budget Start
1998-07-01
Budget End
1999-06-30
Support Year
2
Fiscal Year
1998
Total Cost
Indirect Cost

  Institution

Name
University of Pennsylvania
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104

  Publications

Smith 3rd, Amos B; Wang, Wenyong; Charnley, Adam K et al. (2010) Design, synthesis, and structural analysis of D,L-mixed polypyrrolinones. 1. From nonpeptide peptidomimetics to nanotubes. Org Lett 12:2990-3
Smith 3rd, Amos B; Xiong, Hui; Charnley, Adam K et al. (2010) Design, synthesis, and structural analysis of D,L-mixed polypyrrolinones. 2. Macrocyclic hexapyrrolinones. Org Lett 12:2994-7
Smith 3rd, Amos B; Charnley, Adam K; Harada, Hironori et al. (2006) Design, synthesis, and biological evaluation of monopyrrolinone-based HIV-1 protease inhibitors possessing augmented P2' side chains. Bioorg Med Chem Lett 16:859-63
Smith 3rd, Amos B; Charnley, Adam K; Mesaros, Eugen F et al. (2005) Design, synthesis, and binding affinities of pyrrolinone-based somatostatin mimetics. Org Lett 7:399-402
Smith 3rd, Amos B; Cantin, Louis-David; Pasternak, Alexander et al. (2003) Design, synthesis, and biological evaluation of monopyrrolinone-based HIV-1 protease inhibitors. J Med Chem 46:1831-44
Smith 3rd, A B; Nittoli, T; Sprengeler, P A et al. (2000) Design, synthesis, and evaluation of a pyrrolinone-based matrix metalloprotease inhibitor. Org Lett 2:3809-12