Utilization of the 1,2,5-thiadiazolidin-3-one 1,1 dioxide scaffold in the design of potent inhibitors of serine proteases: SAR studies using carboxylates

A series of carboxylate derivatives based on the 1,2, 5-thiadiazolidin-3-on e 1,1 dioxide and isothiazolidin-3-one 1,1 dioxide scaffolds has been synth esized and the inhibitory profile of these compounds toward human leukocyte elastase (HLE), cathepsin G (Cat G) and proteinase 3 (PR 3) was then deter mined. Most of the compounds were found to be potent, time-dependent inhibi tors of elastase, with some of the compounds exhibiting k(inact)/K-I values as high as 4,928,300 M-1 s(-1). The inhibitory potency of carboxylate deri vatives based on the 1,2,5-thiadiazolidin-3-one I,1 dioxide platform was fo und to be influenced by both the pK(a) and the inherent structure of the le aving group. Proper selection of the primary specificity group (R-1) was fo und to lead to selective inhibition of HLE over Cat G, however, those compo unds that inhibited HLE also inhibited PR 3, albeit less efficiently. The p redictable mode of binding of these compounds suggests that, among closely- related serine proteases, highly selective inhibitors of a particular serin e protease can be fashioned by exploiting subtle differences in their S' su bsites. This study has also demonstrated that the degradative action of ela stase on elastin can be abrogated in the presence of inhibitor 17. (C) 2000 Elsevier Science Ltd. All rights reserved.