Design and synthesis of nonpeptide peptidomimetic inhibitors of renin
Amos B. Smith III
Department of Chemistry, University of Pennsylvania, Philadelphia, Pennsylvania 19104
Search for more papers by this authorRyouichi Akaishi
Department of Chemistry, University of Pennsylvania, Philadelphia, Pennsylvania 19104
Search for more papers by this authorDavid R. Jones
Department of Chemistry, University of Pennsylvania, Philadelphia, Pennsylvania 19104
Search for more papers by this authorTerence P. Keenam
Department of Chemistry, University of Pennsylvania, Philadelphia, Pennsylvania 19104
Search for more papers by this authorMark C. Guzman
Department of Chemistry, University of Pennsylvania, Philadelphia, Pennsylvania 19104
Search for more papers by this authorRyan C. Holcomb
Department of Chemistry, University of Pennsylvania, Philadelphia, Pennsylvania 19104
Search for more papers by this authorPaul A. Sprengeler
Department of Chemistry, University of Pennsylvania, Philadelphia, Pennsylvania 19104
Search for more papers by this authorJohn L. Wood
Department of Chemistry, University of Pennsylvania, Philadelphia, Pennsylvania 19104
Search for more papers by this authorRalph Hirschmann
Department of Chemistry, University of Pennsylvania, Philadelphia, Pennsylvania 19104
Search for more papers by this authorM. Katharine Holloway
Department of Molecular Systems, Merck Research Laboratories, West Point, Pennsylvania 19486
Search for more papers by this authorAmos B. Smith III
Department of Chemistry, University of Pennsylvania, Philadelphia, Pennsylvania 19104
Search for more papers by this authorRyouichi Akaishi
Department of Chemistry, University of Pennsylvania, Philadelphia, Pennsylvania 19104
Search for more papers by this authorDavid R. Jones
Department of Chemistry, University of Pennsylvania, Philadelphia, Pennsylvania 19104
Search for more papers by this authorTerence P. Keenam
Department of Chemistry, University of Pennsylvania, Philadelphia, Pennsylvania 19104
Search for more papers by this authorMark C. Guzman
Department of Chemistry, University of Pennsylvania, Philadelphia, Pennsylvania 19104
Search for more papers by this authorRyan C. Holcomb
Department of Chemistry, University of Pennsylvania, Philadelphia, Pennsylvania 19104
Search for more papers by this authorPaul A. Sprengeler
Department of Chemistry, University of Pennsylvania, Philadelphia, Pennsylvania 19104
Search for more papers by this authorJohn L. Wood
Department of Chemistry, University of Pennsylvania, Philadelphia, Pennsylvania 19104
Search for more papers by this authorRalph Hirschmann
Department of Chemistry, University of Pennsylvania, Philadelphia, Pennsylvania 19104
Search for more papers by this authorM. Katharine Holloway
Department of Molecular Systems, Merck Research Laboratories, West Point, Pennsylvania 19486
Search for more papers by this authorAbstract
The desire to replace the amide backbone of renin inhibitors with a new scaffold led us to explore vinylogous amides (enaminones). An initial attempt proved unsuccessful, a result explained after the fact via docking experiments. Based on this lesson, we designed a different vinylogous amide scaffold which incorportated one or more pyrrolinone rings into the backbone. Three of the four compounds gave IC50s in the 0.6 to 18 μM range. These compounds did not inhibit HIV-1 protease. Taken together, the results reported herein provide insights into the role of hydrogen bonding and steric interactions for binding to renin. © 1994 John Wiley & Sons, Inc.
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