1,2,5-Thiadiazolidin-3-one 1,1-dioxide-based heterocyclic sulfides are potent inhibitors of human tryptase

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Authors
Wong, Tzutshin
Groutas, Christopher S.
Mohan, Swathi
Lai, Zhong
Alliston, Kevin R.
Vu, Nga T.
Schechter, Norman M.
Groutas, William C.
Advisors
Issue Date
2005-04-01
Type
Article
Keywords
Research Support, Non-U.S. Gov't , Research Support, U.S. Gov't, P.H.S.
Research Projects
Organizational Units
Journal Issue
Citation
Archives of biochemistry and biophysics. 2005 Apr 1; 436(1): 1-7.
Abstract

We describe herein the design, synthesis, and in vitro biochemical evaluation of a series of potent, time-dependent inhibitors of the mast cell-derived serine protease tryptase. The inhibitors were readily obtained by attaching various heterocyclic thiols, as well as a basic primary specificity residue P(1), to the 1,2,5-thiadiazolidin-3-one 1,1-dioxide scaffold. The inhibitors were found to be devoid of any inhibitory activity toward a neutral (elastase) or cysteine (papain) protease, however they were also fairly efficient inhibitors of bovine trypsin. The differential inhibition observed with trypsin suggests that enzyme selectivity can be optimized by exploiting differences in the S' subsites of the two enzymes. The results described herein demonstrate the versatility of the heterocyclic scaffold in fashioning mechanism-based inhibitors of neutral, basic, and acidic (chymo)trypsin-like serine proteases.

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Publisher
Elsevier
Journal
Book Title
Series
Archives of biochemistry and biophysics
Arch. Biochem. Biophys.
PubMed ID
DOI
ISSN
0003-9861
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