Rational Design of Potent, Bioavailable, Nonpeptide Cyclic Ureas as HIV Protease Inhibitors

• Published in: Science (American Association for the Advancement of Science) Vol. 263; no. 5145; pp. 380 - 384
• Main Authors: Patrick Y. S. Lam, Jahdav, Prabhakar K., Eyermann, Charles J., Hodge, C. Nicholas, Ru, Yu, Bacheler, Lee T., Meek, James L., Otto, Michael J., Rayner, Marlene M., Wong, Y. Nancy, Chang, Chong-Hwan, Weber, Patricia C., Jackson, David A., Sharpe, Thomas R., Erickson-Viitanen, Susan
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Society for the Advancement of Science 21.01.1994; Amer Assoc Advancement Science; American Association for the Advancement of Science
• Subjects: Active sites; Administration, Oral; AIDS; AIDS/HIV; Analytical, structural and metabolic biochemistry; Animals; Antivirals; Azepines - chemistry; Azepines - metabolism; Azepines - pharmacokinetics; Azepines - pharmacology; Binding Sites; Bioavailability; Biological and medical sciences; Biological Availability; Cell Line; Crystallography, X-Ray; Dogs; Drug Design; Drug Evaluation, Preclinical; Enzymes and enzyme inhibitors; Fundamental and applied biological sciences. Psychology; HIV; HIV (Viruses); HIV 1; HIV Protease - chemistry; HIV Protease - metabolism; HIV Protease Inhibitors - chemistry; HIV Protease Inhibitors - metabolism; HIV Protease Inhibitors - pharmacokinetics; HIV Protease Inhibitors - pharmacology; HIV-1 - drug effects; HIV-1 - physiology; human immunodeficiency virus; Hydrogen Bonding; Hydrogen bonds; Hydrolases; Models, Molecular; Molecular Conformation; Molecular Weight; Molecules; Multidisciplinary Sciences; Nitrogen; Oxygen; Pharmaceutical microbiology; Protease inhibitors; Rats; Recombinant Proteins - chemistry; Recombinant Proteins - metabolism; Science & Technology; Science & Technology - Other Topics; Urea; Virus Replication - drug effects; HOST GUEST COMPLEXATION; ISOSTERE; CRYSTAL-STRUCTURE; RESOLUTION; HUMAN IMMUNODEFICIENCY VIRUS-1; AIDS; LIGAND; BINDING; TYPE-1 PROTEASE; PROTEINASE; Virus; Biological properties; Urea; Enzyme; Cyclic compound; Retroviridae; Enzyme inhibitor; Hydrolases; Lentivirinae; Models; Human immunodeficiency virus; Proteinases
• ISSN: 0036-8075; 1095-9203
• DOI: 10.1126/science.8278812

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.