CYCLOALKYLPYRANONES AND CYCLOALKYLDIHYDROPYRONES AS HIV PROTEASE INHIBITORS - EXPLORING THE IMPACT OF RING SIZE ON STRUCTURE-ACTIVITY-RELATIONSHIPS

Previously, 3-substituted cycloalkylpyranones, such as 2d, have proven to be effective inhibitors of HIV protease. In an initial series of 3 -(1-phenylpropyl) derivatives with various cycloalkyl ring sizes, the cyclooctyl analog was the most potent. We became interested in explori ng the influence of other structural changes, such as substitution on the phenyl ring and saturation of the 5,6-double bond, on the cycloalk yl ring size structure-activity relationship (SAR). Saturation of the 5,6-double bond in the pyrone ring significantly impacts the SAR, alte ring the optimal ring size from eight to six. Substitution of a sulfon amide at the meta position of the phenyl ring dramatically increases t he potency of these inhibitors, but it does not change the optimal rin g size in either the cycloalkylpyranone or the cycloalkyldihydropyrone series. This work has led to the identification of compounds with sup erb binding affinity for the HIV protease (K-i values in the 10-50 pM range). In addition, the cycloalkyldihydropyrones showed excellent ant iviral activity in cell culture, with ED(50) values as low as 1 mu M.