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 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.
Department of Structural, Analytical & Medicinal Chemistry, Pharmacia & Upjohn, Inc., 301 Henrietta Street, Kalamazoo, Michigan 49001, USA.
S R
SR
Turner
J W
JW
Strohbach
R A
RA
Tommasi
P A
PA
Aristoff
P D
PD
Johnson
H I
HI
Skulnick
L A
LA
Dolak
E P
EP
Seest
P K
PK
Tomich
M J
MJ
Bohanon
M M
MM
Horng
J C
JC
Lynn
K T
KT
Chong
R R
RR
Hinshaw
K D
KD
Watenpaugh
M N
MN
Janakiraman
S
S
Thaisrivongs
D000818:Animals; D019380:Anti-HIV Agents / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D002460:Cell Line; D002461:Cell Line, Transformed; D002851:Chromatography, High Pressure Liquid; D018360:Crystallography, X-Ray; D016333:HIV Protease / Q000378:metabolism*; D017320:HIV Protease Inhibitors / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D015497:HIV-1 / Q000187:drug effects / Q000201:enzymology; D006801:Humans; D006860:Hydrogen Bonding; D051379:Mice; D008958:Models, Molecular; D011485:Protein Binding; D011725:Pyridines / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D011753:Pyrones / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013449:Sulfonamides
D019380:Anti-HIV Agents; D017320:HIV Protease Inhibitors; D011725:Pyridines; D011753:Pyrones; D013449:Sulfonamides; D016333:HIV Protease; C107201:tipranavir