A new class of heterocyclic serine protease inhibitors. Inhibition of human leukocyte elastase, porcine pancreatic elastase, cathepsin G, and bovine chymotrypsin A alpha with substituted benzoxazinones, quinazolines, and anthranilates.
The serine proteases human leukocyte (HL) elastase, porcine pancreatic elastase, cathepsin G, and bovine chymotrypsin A alpha are inhibited competitively at pH 7.5 by heterocyclic compounds such as 2-substituted 4H-3,1-benzoxazin-4-ones, 4-quinazolines, and 4-chloroquinazolines, N-substituted phthalimides, and by thioesters of N-acylanthranilic acids. The most potent inhibitors have KI values in the 10(-7)--10(-8) M range. The inhibitors with fluoroalkyl or fluoroacyl substituents are much more potent than the alkyl or acyl derivatives. The quinazolinones, chloroquinazolines, and N-substituted phthalimides are quite specific for HL elastase. With HL elastase, an excellent correlation is observed between pKI and the infrared carbonyl-stretching frequency of the inhibitor. It is proposed that the partially polarized carbonyl group of the inhibitor interacts with a partially polarized charge relay system of the serine protease. The substituents on the inhibitors are proposed to interact with the primary substrate binding site of the serine proteases. The results indicate that it is possible to develop non-peptide small molecules which are specific inhibitors for HL elastase.
D000818:Animals; D056649:Cathepsin G; D002403:Cathepsins / Q000037:antagonists & inhibitors*; D002417:Cattle; D002918:Chymotrypsin / Q000037:antagonists & inhibitors*; D006801:Humans; D007700:Kinetics; D007962:Leukocytes / Q000201:enzymology*; D010078:Oxazines / Q000494:pharmacology*; D010179:Pancreas / Q000201:enzymology*; D010196:Pancreatic Elastase / Q000037:antagonists & inhibitors*; D011480:Protease Inhibitors; D011799:Quinazolines / Q000494:pharmacology*; D012697:Serine Endopeptidases; D013329:Structure-Activity Relationship; D013552:Swine; D062367:ortho-Aminobenzoates / Q000494:pharmacology*
D010078:Oxazines; D011480:Protease Inhibitors; D011799:Quinazolines; D062367:ortho-Aminobenzoates; D002403:Cathepsins; D012697:Serine Endopeptidases; D002918:Chymotrypsin; C534094:CTSG protein, human; D056649:Cathepsin G; D010196:Pancreatic Elastase