Synthesis of an Esterase-Sensitive Cyclic Prodrug of a Model Hexapeptide Having Enhanced Membrane Permeability and Enzymatic Stability Using a 3-(2-Hy

One of the major obstacles to the development of biologically active peptides as clinically useful therapeutic agents has been their low permeation through biological barriers (e.g., intestinal mucosa, blood-brain barrier) and their metabolic lability ( 1 , 2 ). Overcoming these problems is a very contemporary issue for the development of peptide pharmaceuticals. In the preceding chapter, we have indicated that masking the C- and N-terminal polar functional groups of a peptide through cyclization with an acyloxyalkoxy linker can greatly enhance the membrane permeation and metabolic stability of the linear peptide ( 3 ). In this chapter, we wish to report a method for the preparation of esterase-sensitive cyclic prodrugs of peptides by taking advantage of a unique “trimethyl lock”-facilitated lactonization system (Fig. 1 ). Substituted phenol propionic acid derivatives such as 2 , upon unmasking of the hydroxyl group, undergo a facile spontaneous intramolecular cyclization to release the moieties attached to the carboxyl functional group (Fig. 1 ) ( 4 – 6 ). The facile cyclization reaction is the result of the “trimethyl lock”, which was shown earlier to increase the rate of the cyclization reaction in the order of 10 ^5–7 ( 4 – 7 ). The result of such facilitation is that compound 2 has a half-life of only approximately 100 s at room temperature in aqueous solution ( 8 , 9 ). Such systems have been used to develop prodrugs of amines and alcohols ( 8 – 10 ) and redox-sensitive protecting groups of amines ( 11 ).

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