HIV PROTEASE INHIBITORS POSSESSING A NOVEL, HIGH-AFFINITY, AND ACHIRAL P-1' P-2' LIGAND WITH A UNIQUE PATTERN OF IN-VITRO RESISTANCE - IMPORTANCE OF A CONFORMATIONALLY-RESTRICTED TEMPLATE IN THE DESIGN OF ENZYME-INHIBITORS/

Achiral pyran-2-one analogs possessing a 3-S-(2-alkylphenyl) group wer e determined to be high-affinity inhibitors for human immunodeficiency virus (HIV) protease (PR). Crystallographic, modeling, and structure- activity studies led to the 3-S-(2-tert-butylphenyl) moiety as an appa rent optimal group to access the S-2'/S-1' pockets of the enzyme. Furt her optimization led to an inhibitor, utylphenyl)sulfanyl]-4-hydroxy-6 -(3-methylphenyl)- pyran-2-one (14), possessing a K-i of 3 nM. An X-ra y crystallographic structure of an inhibitor, 4-hydroxy-3-[(2-isopropy lphenyl) sulfanyl]-6-phenylpyran-2-one (8), bound to HIV PR showed tha t the 3-S-(2-isopropylphenyl) group occupied the P-2' and P-1' pockets , while other crucial interactions were common to those found with oth er pyran-2-one analogs. The high potency observed for this series may be due, in part, to the restrictions on the intramolecular collapsibil ity of these molecules in aqueous solution, leading to a highly favora ble hydrophobic effect on binding. Herein we report a novel P-2'/P-1' achiral ligand which results in a tight-binding inhibitor that occupie s only three pockets in the enzyme and exhibits a unique pattern of in vitro resistance.