Inhibitors of the protease from human immunodeficiency virus: design

Suvit Thaisrivongs, Alfredo G. Tomasselli, Joseph B. Moon, John Hui, Thomas J. McQuade, Steve R. Turner, Joseph W. Strohbach, W. Jeffrey Howe, W. Gary...
0 downloads 0 Views 4MB Size
2344

J. Med. Chem. 1991,34,2344-2356

Inhibitors of the Protease from Human Immunodeficiency Virus: Design and Modeling of a Compound Containing a Dihydroxyethylene Isostere Insert with High Binding Affinity and Effective Antiviral Activity Suvit Thaisrivongs,*" Alfredo G. Tomasselli,t Joseph B. Moon,$ John Hui,* Thomas J. McQuade,' Steve R. Turner,t Joseph W. Strohbach,t W. Jeffrey Howe,' W. Gary Tarpley,ll and Robert L. Heinriksont Departments of Medicinal Chemistry, Biochemistry, Computational Chemistry, and Cancer & Infectious Diseases Research, Upjohn Laboratories, The Upjohn Company, Kalamazoo, Michigan 49001. Received January 28,1991 The peptidomimetic template and the dihydroxyethylene isostere insert that were applied successfully to the design of renin inhibitors have been extended to the related protease from human immunodeficiency virus (HIV). The present report describes the structure-activity study leading to the identification of an inhibitor with a Ki of