Journal of Medicinal Chemistry p. 3624 - 3637 (1995)
Update date:2022-08-02
Topics:
Thaisrivongs, Suvit
Watenpaugh, Keith D.
Howe, W. Jeffrey
Tomich, Paul K.
Dolak, Lester A.
et al.
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, Ki = 1 μM) 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 functionality appropriately added to the 4-hydroxycoumarin and the 4-hydroxy-2-pyrone templates which resulted in 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 Ki value of 0.0014 μM.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.
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