1,2,5-Thiadiazolidin-3-one 1,1 dioxide: A powerful scaffold for probing the S ' subsites of (chymo)trypsin-like serine proteases

The 1,2,5-thiadiazolidin-3-one 1,1 dioxide scaffold (I) embodies a motif th at allows it to dock to the active site of (chymo)trypsin-like proteases in a predictable and substrate-like fashion. Consequently, inhibitors derived from this heterocyclic scaffold interact with both the S and S' subsites o f an enzyme. Exploitation of binding interactions with both the S and S' su bsites of a target enzyme may lead to compounds with greatly enhanced enzym e selectivity and inhibitory potency. This preliminary report describes the use of a series of compounds having the heterocyclic scaffold linked to va rious amino acids to probe the S' subsites of human leukocyte elastase (HLE ), proteinase 3 (PR 3), and cathepsin G (Cat G). For comparative purposes, a series of compounds derived from a related scaffold, isothiazolidin-3-one 1,1 dioxide (II), was also generated. Several of the compounds were found to be highly potent and selective time-dependent inhibitors of HLE, PR 3, a nd Cat G. (C) 2001 Academic Press.