Targeted libraries

Abstract

One of the most powerful strategies for developing inhibitors of enzymes is to employ a mechanism-based pharmacophore as a key binding element that interacts with the active site of an enzyme. The design of small mol. libraries that display diverse functionality about a minimal mechanism-based pharmacophore enables all members of an enzyme family to be targeted with a single combinatorial synthesis approach. The power of this strategy has been demonstrated by the development of a general synthesis sequence to prep. small mol. libraries based upon the secondary alc. pharmacophore to target aspartyl proteases. In more recent work, a novel synthesis sequence to prep. libraries based upon the ketone carbonyl pharmacophore to target cysteine and serine proteases has been developed. Using these approaches, potent small mol. inhibitors to several therapeutically important aspartyl and cysteine protease targets have been rapidly identified.