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

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Authors
Kuang, Rongze
Epp, Jeffrey B.
Ruan, Sumei
Chong, Lee S.
Venkataraman, Radhika
Tu, Juan
He, Shu
Truong, Tien M.
Groutas, William C.
Issue Date
2000-05-01
Type
Article
Language
eng
Keywords
Research Support, Non-U.S. Gov't , Research Support, U.S. Gov't, P.H.S.
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Abstract

A series of carboxylate derivatives based on the 1,2,5-thiadiazolidin-3-one 1,1 dioxide and isothiazolidin-3-one 1,1 dioxide scaffolds has been synthesized and the inhibitory profile of these compounds toward human leukocyte elastase (HLE), cathepsin G (Cat G) and proteinase 3 (PR 3) was then determined. Most of the compounds were found to be potent, time-dependent inhibitors of elastase, with some of the compounds exhibiting k(inact)/K1 values as high as 4,928,300 M(-1) s(-1). The inhibitory potency of carboxylate derivatives based on the 1,2,5-thiadiazolidin-3-one 1,1 dioxide platform was found to be influenced by both the pKa and the inherent structure of the leaving group. Proper selection of the primary specificity group (R(I)) was found to lead to selective inhibition of HLE over Cat G, however, those compounds that inhibited HLE also inhibited PR 3, albeit less efficiently. The predictable mode of binding of these compounds suggests that, among closely-related serine proteases, highly selective inhibitors of a particular serine protease can be fashioned by exploiting subtle differences in their S' subsites. This study has also demonstrated that the degradative action of elastase on elastin can be abrogated in the presence of inhibitor 17.

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Citation
Bioorganic & medicinal chemistry. 2000 May; 8(5): 1005-16.
Publisher
Elsevier
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PubMed ID
DOI
ISSN
0968-0896
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