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
Groutas, William C. Kuang, Rongze Ruan, Sumei Epp, Jeffrey B. Venkataraman, Radhika Truong, Tien M.
Groutas, William C.
Kuang, Rongze
Ruan, Sumei
Epp, Jeffrey B.
Venkataraman, Radhika
Truong, Tien M.
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Authors
Groutas, William C.
Kuang, Rongze
Ruan, Sumei
Epp, Jeffrey B.
Venkataraman, Radhika
Truong, Tien M.
Kuang, Rongze
Ruan, Sumei
Epp, Jeffrey B.
Venkataraman, Radhika
Truong, Tien M.
Location
Time Period
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Issue Date
1998-06-01
Type
Article
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Keywords
Research Support, U.S. Gov't, P.H.S.
Subjects (LCSH)
Citation
Bioorganic & medicinal chemistry. 1998 Jun; 6(6): 661-71.
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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Publisher
Elsevier
Journal
Book Title
Series
Bioorganic & medicinal chemistry
Bioorg. Med. Chem.
Bioorg. Med. Chem.
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NLM
PubMed ID
DOI
ISSN
0968-0896