Synthesis and Antiviral Activity of a Series of HIV-1 Protease Inhibitors with Functionality Tethered to the P1 or P1′ Phenyl Substituents: X-ray Crystal Structure Assisted Design

Wayne J. Thompson, Paula M.D. Fitzgerald, M. Katharine Holloway, Emilio A. Emini, Paul L. Darke, Brian M. McKeever, William A. Schleif, Julio C. Quintero, Joan A. Zugay, Thomas J. Tucker, John E. Schwering, Carl F. Homnick, Jack Nunberg, James P. Springer, Joel R. Huff

Research output: Contribution to journalArticlepeer-review

Abstract

By tethering of a polar hydrophilic group to the P1 or P1′ substituent of a Phe-based hydroxyethylene isostere, the antiviral potency of a series of HIV protease inhibitors was improved. The optimum enhancement of anti-HIV activity was observed with the 4-morpholinylethoxy substituent. The substituent effect is consistent with a model derived from inhibitor docked in the crystal structure of the native enzyme. An X-ray crystal structure of the inhibited enzyme determined to 2.25 Å verifies the modeling predictions.

Original languageEnglish
Pages (from-to)1685-1701
Number of pages17
JournalJournal of Medicinal Chemistry
Volume35
Issue number10
DOIs
StatePublished - May 1 1992

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