6-Acylamino-2-1[(ethylsulfonyl)oxy]-1H-isoindole-1,3-diones mechanism-based inhibitors of human leukocyte elastase and cathepsin G: effect of chirality in the 6-acylamino substituent on inhibitory potency and selectivity.
Inhibition of human leukocyte elastase(HLE) by a series of 6-acylamino-2-[(ethylsulfonyl)oxy)]-1H-isoindole-1,3-diones was determined and compared to their inhibition of ChT, PPE, and Cat G. The best inhibitor of the series was 6-((1'S)-camphanyl)amino-2-[(ethylsulfonyl) oxy]-1H-isoindole-1,3-dione 5b, with a k(obs)/[I] = 11,000 M(-1) s(-1). This study revealed that HLE shows a preference for the S stereochemistry and tolerates hydrophobic substituents in the Sn' binding sites. Molecular modeling of non-covalent HLE-inhibitor complexes was used as a tool to investigate our binding model. Buffer stability assays reveal that these compounds are susceptible to hydrolysis at physiological pH.
Vagnoni
L M
LM
Department of Pharmaceutical Chemistry, College of Pharmacy, Rutgers University, Piscataway, NJ 08854, USA.
Gronostaj
M
M
Kerrigan
J E
JE
D000818:Animals; D056649:Cathepsin G; D002403:Cathepsins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D002417:Cattle; D002918:Chymotrypsin / Q000037:antagonists & inhibitors; D004355:Drug Stability; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology; D006801:Humans; D007211:Indoles / Q000138:chemical synthesis / Q000494:pharmacology*; D007700:Kinetics; D019272:Leukocyte Elastase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D008958:Models, Molecular; D010196:Pancreatic Elastase / Q000037:antagonists & inhibitors / Q000378:metabolism; D012697:Serine Endopeptidases; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013379:Substrate Specificity; D013552:Swine; D013816:Thermodynamics
D004791:Enzyme Inhibitors; D007211:Indoles; D002403:Cathepsins; D012697:Serine Endopeptidases; D002918:Chymotrypsin; C117608:alpha-chymotrypsin; C534094:CTSG protein, human; D056649:Cathepsin G; D010196:Pancreatic Elastase; D019272:Leukocyte Elastase