Design of orally bioavailable, symmetry-based inhibitors of HIV protease

• Published in: Bioorganic & medicinal chemistry 1994-09, Vol.2 (9), p.847-858
• Main Authors: Kempf, Dale J., Marsh, Kennan C., Fino, Lynnmarie Codacovi, Bryant, Pamela, Craig-Kennard, Adrienne, Sham, Hing L., Zhao, Chen, Vasavanonda, Sudthida, Kohlbrenner, William E., Wideburg, Norman E., Saldivar, Ayda, Green, Brian E., Herrin, Thomas, Norbeck, Daniel W.
• Format: Article
• Language: English
• Subjects: Administration, Oral; AIDS/HIV; Amino Acid Sequence; Biological Availability; Cells, Cultured; HIV Protease Inhibitors - chemical synthesis; HIV Protease Inhibitors - pharmacokinetics; HIV Protease Inhibitors - pharmacology; HIV-1 - drug effects; HIV-1 - enzymology; Humans; Lymphocytes - virology; Molecular Sequence Data; Structure-Activity Relationship
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/S0968-0896(00)82036-2

A series of novel inhibitors of HIV-1 protease with excellent oral bioavailability is described. Differential acylation of the two amino groups of symmetry-based diamine core groups 2– 5 led to unsymmetrically substituted inhibitors 17– 43, many of which inhibited HIV protease at subnanomolar concentrations. Anti-HIV activity in vitro was observed at 0.1–1 μM. A systematic evaluation of the pharmacokinetic behavior of these inhibitors in rats identified the influence of aqueous solubility, molecular size and hydrogen-bonding functionality. Compound 30 (A-80987) was selected for further evaluation based on a favorable C max/ED 50 ratio (> 20) and half-life (> 2 h). A series of novel, symmetry-based inhibitors of HIV-1 protease with excellent oral bioavailability is described. Systematic evaluation identified the influence of aqueous solubility, molecular size and hydrogen-bonding functionality upon the pharmacokinetic behavior of these inhibitors in rats