Synthesis and evaluation of pyridyl analogs of L-735,524: Potent HIV-1 protease inhibitors

Two series of HIV protease inhibitors possessing a hydroxyaminopentanamide transition state isostere were prepared and evaluated in peptide cleavage and whole cell assays. These were found to be effective in low concentrations at halting the spread of the AIDS virus, and a number of these inhibitors...

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Published in:Bioorganic & medicinal chemistry letters 1994-12, Vol.4 (23), p.2769-2774
Main Authors: Dorsey, Bruce D., McDaniel, Stacey L., Levin, Rhonda B., Vacca, Joseph P., Darke, Paul L., Zuga, Joan A., Emini, Emilio A., Schleif, William A., Lin, Jiunn H., Chen, I-W., Holloway, M.Katharine, Anderson, Paul S., Huff, Joel R.
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Language:English
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Summary:Two series of HIV protease inhibitors possessing a hydroxyaminopentanamide transition state isostere were prepared and evaluated in peptide cleavage and whole cell assays. These were found to be effective in low concentrations at halting the spread of the AIDS virus, and a number of these inhibitors were also found to provide reasonable plasma levels after oral dosing in animal models. The most promising, L-748,496 is potent (IC 50 = 0.12 nM and IC 95 = 6-12 nM) and comparable to L-735,524, which is currently in phase II human clinical trials. Graphic
ISSN:0960-894X
1464-3405
DOI:10.1016/S0960-894X(01)80592-8