POTENT AND SPECIFIC-INHIBITION OF HUMAN-LEUKOCYTE ELASTASE, CATHEPSIN-G AND PROTEINASE-3 BY SULFONE DERIVATIVES EMPLOYING THE 1,2,5-THIADIAZOLIDIN-3-ONE 1,1-DIOXIDE SCAFFOLD

This paper describes the results of structure-activity relationship st udies in a series of heterocyclic mechanism-based inhibitors based on the 1,2,5-thiadiazolidin-3-one 1,1 dioxide scaffold I and capable of i nteracting with the S-n and S-n' subsites of a serine proteinase. Sulf one derivatives of I were found to be highly effective, time-dependent inhibitors of human leukocyte elastase (HLE), cathepsin G (Cat G) and proteinase 3 (PR 3). The judicious selection of an R-1 group (accommo dated at the primary specificity site S-1) that is based on the known substrate specificity of a target serine proteinase, was found to yiel d highly selective inhibitors. The presence of a benzyl group (R-2 = b enzyl) at the S-2 subsite was found to lead to a pronounced enhancemen t in inhibitory potency. Furthermore, the effective use of computer gr aphics and modeling has led to the design of potent, water-soluble inh ibitors. The results of these studies demonstrate that the 1,2,5-thiad iazolidin-3-one 1,1, dioxide platform provides an effective means for appending recognition elements in a well-defined vector relationship, and in fashioning highly-selective and potent inhibitors of serine pro teinases. (C) 1998 Elsevier Science Ltd. All rights reserved.