NONPEPTIDIC HIV PROTEASE INHIBITORS - 4-HYDROXY-PYRAN-2-ONE INHIBITORS WITH FUNCTIONAL TETHERS TO P-1 PHENYL RING TO REACH S-3 POCKET OF THE ENZYME

A systematic study of tethering various groups on 6-phenyl ring of xy- 6-phenyl-3-[(2-isopropylphenyl)thio]pyran-2-one was performed to incre ase the binding affinity with HIV protease. This tethering approach wa s aimed to fill S-3 pocket of the enzyme. Thus, tethering hydrophilic groups resulted in more potent inhibitors. Similarly, various aromatic hydrophobic rings as well as heterocyclic rings were explored as teth ering substitutents to alter the physical properties as well as to enh ance the binding affinity with HIV protease. Inhibitor 24, ]-6-[4-(3-p yridinylmethoxy)phenyl]-2H-pyran-2-one, was evaluated as a prototypic lead structure to study various physical as well as pharmacological pr operties of this class of HIV protease inhibitors. (C) 1996 Academic P ress, Inc.