| Abstract
| - Previously, 3-substituted cycloalkylpyranones, such as2d, have proven to be effective inhibitorsof HIV protease. In an initial series of 3-(1-phenylpropyl)derivatives with various cycloalkylring sizes, the cyclooctyl analog was the most potent. We becameinterested in exploring theinfluence of other structural changes, such as substitution on thephenyl ring and saturationof the 5,6-double bond, on the cycloalkyl ring sizestructure−activity relationship (SAR).Saturation of the 5,6-double bond in the pyrone ring significantlyimpacts the SAR, alteringthe optimal ring size from eight to six. Substitution of asulfonamide at the meta position ofthe phenyl ring dramatically increases the potency of these inhibitors,but it does not changethe optimal ring size in either the cycloalkylpyranone or thecycloalkyldihydropyrone series.This work has led to the identification of compounds with superbbinding affinity for the HIVprotease (Ki values in the 10−50 pM range).In addition, the cycloalkyldihydropyrones showedexcellent antiviral activity in cell culture, with ED50values as low as 1 μM.
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