Potent inhibition of serine proteases by heterocyclic sulfide derivatives of 1,2,5-thiadiazolidin-3-one 1,1 dioxide

The existence of subtle differences in the S-n' subsites of closely-related (chymo)trypsin-like serine proteases, and the fact that the 1,2,5-thiadiaz olidin-3-one 1,1 dioxide scaffold docks to the active site of (chymo)trypsi n-like enzymes in a substrate-like fashion, suggested that the introduction of recognition elements that can potentially interact with the S-n' subsit es of these proteases might provide an effective means for optimizing enzym e potency and selectivity. Accordingly, a series of heterocyclic sulfide de rivatives based on the 1,2,5-thiadiazolidin-3-one 1,1 dioxide scaffold (I) was synthesized and the inhibitory activity and selectivity of these compou nds toward human leukocyte elastase (HLE), proteinase 3 (PR 3) and cathepsi n G (Cat G) were then determined. Compounds with P-1 = isobutyl were found to be potent, time-dependent inhibitors of HLE and, to a lesser extent PR 3 , while those with P-1 = benzyl inactivated Cat G rapidly and irreversibly. This study has demonstrated that 1,2,5-thiadiazolidin-3-one 1,1 dioxide-ba sed heterocyclic sulfides are effective inhibitors of (chymo)trypsin-like s erine proteases. (C) 2000 Elsevier Science Ltd. All rights reserved.