Combinatorial Synthesis of Transition State Mimetic Inhibitor Using Asymmetric Aldol, Reaction

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An efficient method has been developed for the first solid phase synthesis of HTLV 1 protease inhibitors that contain hydroxyethylamine isostere as transitionslate mimetic. The synthetic procedure was designed to allow the evaluation of stereostmctureactivity relationships at the scissile site. All the possible configurations at the hydroxy and side chainbearing asymmetric centers of the isostere were constructed by an esterderived asymmetric aldol reaction. Each inhibitor containing the isostere backbone was synthesized on solid support using the newly developed succinate ester linker. The configuration at the hydroxy and side chainbearing asymmetric center showed remarkable effects on the inhibitory activity. The K_i value changed with approximately two orders of magnitude. This approach enables an efficient preparation of the inhibitors containing a transitionstate mimetic