A novel strategy for designing irreversible inhibitors of metalloproteases: acetals as latent electrophiles that interact with catalytic nucleophile at the active site

A new strategy for design of irreversible inactivators for carboxypeptidase A (CPA), a prototypic zinc protease, has been developed by exploiting the property of acetals to generate an oxacarbenium ion intermediate in the conversion into the corresponding carbonyl compounds. The design strategy is exemplified by 2-benzyl-5-alkyl-3,5-dioxapentanoic acids (1a-c). Interestingly, (R)-1b is slightly more potent than an (S)-1b as an inactivator of CPA.