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Design, synthesis, and evaluation of tetrahydropyrimidinones as an example of a general approach to nonpeptide HIV protease inhibitors.
- Source :
-
Journal of medicinal chemistry [J Med Chem] 1997 May 23; Vol. 40 (11), pp. 1707-9. - Publication Year :
- 1997
-
Abstract
- Re-examination of the design of the cyclic urea class of HIV protease (HIVPR) inhibitors suggests a general approach to designing novel nonpeptide cyclic HIVPR inhibitors. This process involves the inversion of the stereochemical centers of the core transition-state isostere of the linear HIVPR inhibitors and cyclization of the resulting core using an appropriate cyclizing reagent. As an example, this process is applied to the diamino alcohol class of HIVPR inhibitors to give tetrahydropyrimidinones. Conformational analysis of the tetrahydropyrimidinones and modeling of its interaction with the active site of HIVPR suggested modifications which led to very potent inhibitors of HIVPR (24 with a Ki = 0.018 nM). The X-ray crystallographic structure of the complex of 24 with HIVPR confirms the analysis and modeling predictions. The example reported in this study and other examples that are cited indicate that this process may be generally applicable to other linear inhibitors.
- Subjects :
- Binding Sites
Computer Simulation
Crystallography, X-Ray
Cyclization
HIV Protease Inhibitors chemistry
HIV Protease Inhibitors pharmacology
Hydrogen Bonding
Models, Molecular
Molecular Conformation
Molecular Structure
Oximes chemistry
Oximes pharmacology
Pyrimidinones chemistry
Pyrimidinones pharmacology
Drug Design
HIV Protease Inhibitors chemical synthesis
Oximes chemical synthesis
Pyrimidinones chemical synthesis
Subjects
Details
- Language :
- English
- ISSN :
- 0022-2623
- Volume :
- 40
- Issue :
- 11
- Database :
- MEDLINE
- Journal :
- Journal of medicinal chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 9171880
- Full Text :
- https://doi.org/10.1021/jm970081i