Article ID | Journal | Published Year | Pages | File Type |
---|---|---|---|---|
9882260 | Archives of Biochemistry and Biophysics | 2005 | 7 Pages |
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 P1, 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 Sâ² 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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Authors
Tzutshin Wong, Christopher S. Groutas, Swathi Mohan, Zhong Lai, Kevin R. Alliston, Nga Vu, Norman M. Schechter, William C. Groutas,