TIPRANAVIR (PNU-140690) - A POTENT, ORALLY BIOAVAILABLE NONPEPTIDIC HIV PROTEASE INHIBITOR OF THE 5,6-DIHYDRO-4-HYDROXY-2-PYRONE SULFONAMIDE CLASS

A broad screening program previously identified phenprocoumon (1) as a small molecule template for inhibition of HIV protease. Subsequent mo dification of this lead through iterative cycles of structure-based de sign 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-act ivity relationships described in this paper. Crystallographic studies provided further information on important binding interactions respons ible 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 thi s compound (PNU-140690, Tipranavir) for treatment of HIV infection are currently underway.