S. Thaisrivongs et al., STRUCTURE-BASED DESIGN OF HIV PROTEASE INHIBITORS - 5,6-DIHYDRO-4-HYDROXY-2-PYRONES AS EFFECTIVE, NONPEPTIDIC INHIBITORS, Journal of medicinal chemistry, 39(23), 1996, pp. 4630-4642
From a broad screening program, the 4-hydroxycoumarin phenprocoumon (I
) was previously identified as a lead template with HIV protease inhib
itory activity. The crystal structure of phenprocoumon/HIV protease co
mplex initiated a structure-based design effort that initially identif
ied the 4-hydroxy-2-pyrone U-96988 (II) as a first-generation clinical
candidate for the potential treatment of HIV infection. Based upon th
e crystal structure of the 4-hydroxy-2-pyrone III/HIV protease complex
, a series of analogues incorporating a 5,6-dihydro-4-hydroxy-2-pyrone
template were studied. It was recognized that in addition to having t
he required pharmacophore (the 4-hydroxy group with hydrogen-bonding i
nteraction with the two catalytic aspartic acid residues and the lacto
ne moiety replacing the ubiquitous water molecule in the active site),
these 5,6-dihydro-4-hydroxy-2-pyrones incorporated side chains at the
C-6 position that appropriately extended into the S-1' and S-2' subsi
tes of the enzyme active site. The crystal structures of a number of r
epresentative 5,6-dihydro-4-hydroxy-2-pyrones complexed with the HIV p
rotease were also determined to provide better understanding of the in
teraction between the enzyme and these inhibitors to aid the structure
-based drug design effort. The crystal structures of the ligands in th
e enzyme active site did not always agree with the conformations expec
ted from experience with previous pyrone inhibitors. This is likely du
e to the increased flexibility of the dihydropyrone ring. From this st
udy, compound XIX exhibited reasonably high enzyme inhibitory activity
(K-i = 15 nM) and showed antiviral activity (IC50 = 5 mu M) in the ce
ll-culture assay. This result provided a research direction which led
to the discovery of active 5,6-dihydro-4-hydroxy-2-pyrones as potentia
l agents for the treatment of HIV infection.