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Rational design of potent, bioavailable, nonpeptide cyclic ureas as HIV protease inhibitors.
- Source :
-
Science (New York, N.Y.) [Science] 1994 Jan 21; Vol. 263 (5145), pp. 380-4. - Publication Year :
- 1994
-
Abstract
- Mechanistic information and structure-based design methods have been used to design a series of nonpeptide cyclic ureas that are potent inhibitors of human immunodeficiency virus (HIV) protease and HIV replication. A fundamental feature of these inhibitors is the cyclic urea carbonyl oxygen that mimics the hydrogen-bonding features of a key structural water molecule. The success of the design in both displacing and mimicking the structural water molecule was confirmed by x-ray crystallographic studies. Highly selective, preorganized inhibitors with relatively low molecular weight and high oral bioavailability were synthesized.
- Subjects :
- Administration, Oral
Animals
Azepines metabolism
Azepines pharmacokinetics
Azepines pharmacology
Binding Sites
Biological Availability
Cell Line
Crystallography, X-Ray
Dogs
Drug Evaluation, Preclinical
HIV Protease chemistry
HIV Protease metabolism
HIV Protease Inhibitors metabolism
HIV Protease Inhibitors pharmacokinetics
HIV Protease Inhibitors pharmacology
HIV-1 drug effects
HIV-1 physiology
Hydrogen Bonding
Models, Molecular
Molecular Conformation
Molecular Weight
Rats
Recombinant Proteins chemistry
Recombinant Proteins metabolism
Urea
Virus Replication drug effects
Azepines chemistry
Drug Design
HIV Protease Inhibitors chemistry
Subjects
Details
- Language :
- English
- ISSN :
- 0036-8075
- Volume :
- 263
- Issue :
- 5145
- Database :
- MEDLINE
- Journal :
- Science (New York, N.Y.)
- Publication Type :
- Academic Journal
- Accession number :
- 8278812
- Full Text :
- https://doi.org/10.1126/science.8278812