Tipranavir (PNU-140690):  A Potent, Orally Bioavailable Nonpeptidic HIV Protease Inhibitor of the 5,6-Dihydro-4-hydroxy-2-pyrone Sulfonamide Class

• Published in: Journal of medicinal chemistry 1998-08, Vol.41 (18), p.3467-3476
• Main Authors: Turner, Steve R, Strohbach, Joseph W, Tommasi, Ruben A, Aristoff, Paul A, Johnson, Paul D, Skulnick, Harvey I, Dolak, Lester A, Seest, Eric P, Tomich, Paul K, Bohanon, Michael J, Horng, Miao-Miao, Lynn, Janet C, Chong, Kong-Teck, Hinshaw, Roger R, Watenpaugh, Keith D, Janakiraman, Musiri N, Thaisrivongs, Suvit
• Format: Article
• Language: English
• Subjects: AIDS/HIV; Animals; Anti-HIV Agents - chemistry; Anti-HIV Agents - metabolism; Anti-HIV Agents - pharmacology; Antibiotics. Antiinfectious agents. Antiparasitic agents; Antiviral agents; Biological and medical sciences; Cell Line; Cell Line, Transformed; Chromatography, High Pressure Liquid; Crystallography, X-Ray; HIV Protease - metabolism; HIV Protease Inhibitors - chemistry; HIV Protease Inhibitors - metabolism; HIV Protease Inhibitors - pharmacology; HIV-1 - drug effects; HIV-1 - enzymology; Human immunodeficiency virus; Humans; Hydrogen Bonding; Medical sciences; Mice; Models, Molecular; Pharmacology. Drug treatments; Protein Binding; Pyridines - chemistry; Pyridines - metabolism; Pyridines - pharmacology; Pyrones - chemistry; Pyrones - metabolism; Pyrones - pharmacology; Stereoisomerism; Structure-Activity Relationship; tipranavir
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm9802158

A broad screening program previously identified phenprocoumon (1) as a small molecule template for inhibition of HIV protease. Subsequent modification of this lead through iterative cycles of structure-based design led to the activity enhancements of pyrone and dihydropyrone ring systems (II and V) and amide-based substitution (III). Incorporation of sulfonamide substitution within the dihydropyrone template provided a series of highly potent HIV protease inhibitors, with structure−activity relationships described in this paper. Crystallographic studies provided further information on important binding interactions responsible for high enzymatic binding. These studies culminated in compound VI, which inhibits HIV protease with a K i value of 8 pM and shows an IC90 value of 100 nM in antiviral cell culture. Clinical trials of this compound (PNU-140690, Tipranavir) for treatment of HIV infection are currently underway.