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Nonpeptide cyclic cyanoguanidines as HIV-1 protease inhibitors: synthesis, structure-activity relationships, and X-ray crystal structure studies.
- Source :
-
Journal of medicinal chemistry [J Med Chem] 1998 Apr 23; Vol. 41 (9), pp. 1446-55. - Publication Year :
- 1998
-
Abstract
- Comparison of the high-resolution X-ray structures of the native HIV-1 protease and its complexes with the inhibitors suggested that the enzyme flaps are flexible. The movement at the tip of the flaps could be as large as 7 A. On the basis of this observation, cyclic cyanoguanidines have been designed, synthesized, and evaluated as HIV-1 protease (PR) inhibitors. Cyclic cyanoguanidines were found to be very potent inhibitors of HIV-1 protease. The choice of cyclic cyanoguanidines over cyclic guanidines was based on the reduced basicity of the former. X-ray structure studies of the HIV PR complex with cyclic cyanoguanidine demonstrated that in analogy to cyclic urea, cyclic cyanoguanidines also displace the unique structural water molecule. The structure-activity relationship of the cyclic cyanoguanidines is compared with that of the corresponding cyclic urea analogues. The differences in binding constants of the two series of compounds have been rationalized using high-resolution X-ray structure information.
- Subjects :
- Cell Line
Crystallography, X-Ray
HIV Protease chemistry
HIV-1 enzymology
Humans
Hydrogen Bonding
Models, Molecular
Structure-Activity Relationship
Urea analogs & derivatives
Urea chemistry
Anti-HIV Agents chemical synthesis
Anti-HIV Agents chemistry
Anti-HIV Agents metabolism
Anti-HIV Agents pharmacology
Guanidines chemical synthesis
Guanidines chemistry
Guanidines metabolism
Guanidines pharmacology
HIV Protease metabolism
HIV Protease Inhibitors chemical synthesis
HIV Protease Inhibitors chemistry
HIV Protease Inhibitors metabolism
HIV Protease Inhibitors pharmacology
HIV-1 drug effects
Subjects
Details
- Language :
- English
- ISSN :
- 0022-2623
- Volume :
- 41
- Issue :
- 9
- Database :
- MEDLINE
- Journal :
- Journal of medicinal chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 9554878
- Full Text :
- https://doi.org/10.1021/jm970524i