title: Inhibition of human mast cell tryptase by benzamidine derivatives.
abstract: Considerable circumstantial evidence has been provided by in vitro studies that tryptase (EC 3.4.21.59), a neutral serine proteinase stored in large amounts in mast cell granules, may play an important pathogenetic role in mast cell-dependent diseases. However, a definitive role has not yet been ascribed to this trypsin-like enzyme with restricted substrate specificity as natural or synthetic inhibitors of tryptase applicable for in vivo studies are not available so far. Therefore, we have studied structure-activity relationships for inhibition of tryptase by benzamidine derivatives, compounds known to be potent inhibitors of various trypsin-like enzymes. Among the benzamidine derivatives 4-amidinophenylpyruvic acid exerts a striking inhibitory activity with a Ki of 0.71 mumol/l. Several additional inhibitors of tryptase with Ki values in the micromolar range were found among bis-benzamidines. Derivatives of N alpha-arylsulfonyl-omega-amidinophenyl-alpha-aminoalkylcarboxylic acids are only weak inhibitors of tryptase, although members of this group are potent and selective inhibitors of several other trypsin-like enzymes. Comparison of the inhibition of tryptase and trypsin revealed that the affinities of the benzamidine derivatives to both proteinases are closely correlated (correlation coefficient r = 0.702; n = 37; p < 0.001). These results demonstrate that 4-amidinophenylpyruvic acid may be useful as a pharmacologic tool for the investigation of the (patho)physiological role of tryptase. In addition, benzamidine derivatives may be applicable to probe the active site topography of tryptase isoenzymes.
authors.affiliation: Institut für Pharmakologie und Toxikologie, Medizinische Akademie Erfurt, Germany.
authors.forename: J
authors.initials: J
authors.lastname: Stürzebecher
authors.forename: D
authors.initials: D
authors.lastname: Prasa
authors.forename: C P
authors.initials: CP
authors.lastname: Sommerhoff
mesh_terms: D001550:Benzamidines / Q000494:pharmacology*; D001665:Binding Sites; D053818:Chymases; D006801:Humans; D008407:Mast Cells / Q000201:enzymology*; D010667:Phenylpyruvic Acids / Q000494:pharmacology; D012697:Serine Endopeptidases / Q000378:metabolism*; D015842:Serine Proteinase Inhibitors / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D053802:Tryptases
chemical_list: D001550:Benzamidines; D010667:Phenylpyruvic Acids; D015842:Serine Proteinase Inhibitors; C006492:amidinophenylpyruvic acid; D012697:Serine Endopeptidases; C083294:chymase 2; D053818:Chymases; D053802:Tryptases