Tipranavir (PNU-140690): a potent, orally bioavailable nonpeptidic HIV protease inhibitor of the 5,6-dihydro-4-hydroxy-2-pyrone sulfonamide class.

Abstract:

: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 Ki 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.

journal_name

J Med Chem

authors

Turner SR,Strohbach JW,Tommasi RA,Aristoff PA,Johnson PD,Skulnick HI,Dolak LA,Seest EP,Tomich PK,Bohanon MJ,Horng MM,Lynn JC,Chong KT,Hinshaw RR,Watenpaugh KD,Janakiraman MN,Thaisrivongs S

doi

10.1021/jm9802158

subject

Has Abstract

pub_date

1998-08-27 00:00:00

pages

3467-76

issue

18

eissn

0022-2623

issn

1520-4804

pii

jm9802158

journal_volume

41

pub_type

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