Anionic inhibitors of pancreatic and leukocyte elastase. Alkylamides of 3-carboxypropionyl- and 4-carboxybutyrylalanine peptides.
Low-molecular inhibitors of pancreatic and leukocyte elastase were synthesized of the general formula X-[Ala]n-A [X = Suc and Glt, A = ethylamide, n = 1, 2, 3 and 4; for n = 2 X = H and A = (2-phenylethyl)amide] and of the formula X-[Ala]3-A (X = H, Suc and Glt, A = methyl-, ethyl-, propyl-, isopropyl-, butyl-, isobutyl-, (2-phenylethyl)- and diethylamide; for A = ethylamide, X = maleyl or acetyl). Inhibition constants Ki of these pancreatic and leukocyte elastase inhibitors were determined using the chromogenic substrates Suc-[Ala]4-Nan or Glt-[Ala]4-Nan and Glt-[Ala]3-Val-Nan, respectively. The series of anionic inhibitors containing three alanine residues has the best inhibitory properties. Of the acyl groups, 4-carboxybutyryl appears most advantageous, propylamide is the most suitable of alkylamides for pancreatic elastase, and isobutylamide for leukocyte elastase. Peptides containing a free amino group show an inhibition for pancreatic elastase lower by one order than that of the corresponding acylated derivatives. Glt-[Ala]3-NH-Pr is the best inhibitor of pancreatic elastase with Ki = 0.003mM and Suc-[Ala]3-NH-iBu is the best inhibitor of leukocyte elastase with Ki = 0.7mM.
D000818:Animals; D066298:In Vitro Techniques; D007700:Kinetics; D007962:Leukocytes / Q000201:enzymology; D009842:Oligopeptides / Q000494:pharmacology*; D010179:Pancreas / Q000201:enzymology; D010196:Pancreatic Elastase / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship; D013379:Substrate Specificity; D013552:Swine
D009842:Oligopeptides; D010196:Pancreatic Elastase