Structure-based design of novel HIV protease inhibitors: carboxamide-containing 4-hydroxycoumarins and 4-hydroxy-2-pyrones as potent nonpeptidic inhibitors.
The low oral bioavailability and rapid biliary excretion of peptide-derived HIV protease inhibitors have limited their utility as potential therapeutic agents. Our broad screening program to discover nonpeptidic HIV protease inhibitors had previously identified compound II (phenprocoumon, K(i) = 1 muM) as a lead template. Crystal structures of HIV protease complexes containing the peptide-derived inhibitor I (1-(naphthoxyacetyl)-L-histidyl-5(S)-amino-6-cyclohexyl-3 (R),4(R)-dihydroxy-2(R)-isopropylhexanoyl-L-isoleucine N-(2-pyridylmethyl)amide) and nonpeptidic inhibitors, such as phenprocoumon (compound II), provided a rational basis for the structure-based design of more active analogues. This investigation reports on the important finding of a carboxamide functionally appropriately added to the 4-hydroxycoumarin and the 4-hydroxy-2-pyrone templates which resulted in a new promising series of nonpeptidic HIV protease inhibitors with improved enzyme-binding affinity. The most active diastereomer of the carboxamide-containing compound XXIV inhibited HIV-1 protease with a K(i) value of 0.0014 muM. This research provides a new design direction for the discovery of more potent HIV protease inhibitors as potential therapeutic agents for the treatment of HIV infection.
Thaisrivongs
S
S
Upjohn Laboratories, Kalamazoo, Michigan 49001, USA.
Watenpaugh
K D
KD
Howe
W J
WJ
Tomich
P K
PK
Dolak
L A
LA
Chong
K T
KT
Tomich
C C
CC
Tomasselli
A G
AG
Turner
S R
SR
Strohbach
J W
JW
D015110:4-Hydroxycoumarins / Q000737:chemistry / Q000494:pharmacology*; D000595:Amino Acid Sequence; D001665:Binding Sites; D002460:Cell Line; D003196:Computer Graphics; D018360:Crystallography, X-Ray; D017320:HIV Protease Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D015497:HIV-1 / Q000201:enzymology*; D015498:HIV-2 / Q000201:enzymology; D006801:Humans; D008969:Molecular Sequence Data; D011753:Pyrones / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
D015110:4-Hydroxycoumarins; D017320:HIV Protease Inhibitors; D011753:Pyrones; C068805:4-hydroxycoumarin