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

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Authors
Groutas, William C.
Kuang, Rongze
Ruan, Sumei
Epp, Jeffrey B.
Venkataraman, Radhika
Truong, Tien M.
Issue Date
1998-06-01
Type
Article
Language
eng
Keywords
Research Support, U.S. Gov't, P.H.S.
Research Projects
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Abstract

This paper describes the results of structure-activity relationship studies 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 interacting with the Sn and Sn' subsites of a serine proteinase. Sulfone 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 R1 group (accommodated at the primary specificity site S1) that is based on the known substrate specificity of a target serine proteinase, was found to yield highly selective inhibitors. The presence of a benzyl group (R2 = benzyl) at the S2 subsite was found to lead to a pronounced enhancement in inhibitory potency. Furthermore, the effective use of computer graphics and modeling has led to the design of potent, water-soluble inhibitors. The results of these studies demonstrate that the 1,2,5-thiadiazolidin-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 proteinases.

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Citation
Bioorganic & medicinal chemistry. 1998 Jun; 6(6): 661-71.
Publisher
Elsevier
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Issue
PubMed ID
DOI
ISSN
0968-0896
EISSN