SYNTHETIC CHEMICAL DIVERSITY - SOLID-PHASE SYNTHESIS OF LIBRARIES OF C-2 SYMMETRICAL INHIBITORS OF HIV PROTEASE CONTAINING DIAMINO DIOL ANDDIAMINO ALCOHOL CORES

Solid phase synthesis of non-oligomeric organic compounds has been pur sued for high-efficiency generation of large numbers of structurally d iverse compounds for drug screening. Known as chemical diversity libra ries or combinatorial libraries (when the synthesis is carried out in a combinatorial fashion), these compounds can be used for de novo disc overy of drug leads or for expedient structure-activity relationship ( SAR) studies. To expand the scope of solid phase synthesis beyond the capability of the traditional method of solid phase synthesis for pept ides, a strategy was developed for bi-directional solid phase synthesi s starting with diamino alcohol or diamino diol core structures. The s trategy relies on using bifunctional linkers to modify the core struct ures, simultaneously protecting the hydroxyl group or the diol moiety of the core and providing a carboxyl group for attachment of the modif ied cores to a solid support. The two NH2 groups of the modified cores attached to the solid support were then deprotected and reacted with a wide variety of amine-reactive reagents (carboxylic acids, sulfonyl chlorides, isocyanates, chloroformates, etc.) to extend the molecule i n both directions. This strategy was successfully applied to automated parallel synthesis of a library of C-2 symmetric inhibitors of HIV pr otease containing the known symmetry-based diamino diol and diamino al cohol core structures, thus enabling expedient access of large numbers of analogs in this series. A library of over 300 discrete compounds w as synthesized using this methodology in order to identify potent (IC5 0 < 100 nM) HIV protease inhibitors with reduced size. This paper desc ribes the technical aspects of this technology.