1,2,5-Thiadiazolidin-3-one 1,1-dioxide-based heterocyclic sulfides are potent inhibitors of human tryptase.
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.
Wong
Tzutshin
T
Department of Chemistry, Wichita State University, Wichita, KS 67260, USA.
Groutas
Christopher S
CS
Mohan
Swathi
S
Lai
Zhong
Z
Alliston
Kevin R
KR
Vu
Nga
N
Schechter
Norman M
NM
Groutas
William C
WC
D000818:Animals; D002417:Cattle; D002918:Chymotrypsin / Q000737:chemistry; D003499:Cyclic S-Oxides / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D006571:Heterocyclic Compounds / Q000494:pharmacology; D006801:Humans; D019272:Leukocyte Elastase / Q000037:antagonists & inhibitors / Q000187:drug effects; D010206:Papain / Q000037:antagonists & inhibitors; D012697:Serine Endopeptidases / Q000187:drug effects / Q000378:metabolism*; D015842:Serine Proteinase Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology*; D013440:Sulfides / Q000494:pharmacology*; D013830:Thiadiazoles / Q000138:chemical synthesis / Q000494:pharmacology*; D013997:Time Factors; D053802:Tryptases
D003499:Cyclic S-Oxides; D006571:Heterocyclic Compounds; D015842:Serine Proteinase Inhibitors; D013440:Sulfides; D013830:Thiadiazoles; D012697:Serine Endopeptidases; D002918:Chymotrypsin; D019272:Leukocyte Elastase; D053802:Tryptases; D010206:Papain