Peptidyl carbamates as novel elastase inhibitors: structure-activity relationship studies.
Twenty-six novel peptidyl carbamates and thiocarbamates were synthesized and evaluated as elastase inhibitors. Eighteen compounds inhibited porcine pancreatic elastase, whereas only eleven of the newly synthesized compounds inhibited human leukocyte elastase. Neither of the other serine dependent proteases, trypsin or chymotrypsin, were affected by any of the active inhibitors. Structure-activity relationship studies indicated that inhibition was dependent on P1 and P'1 substitution as well as on the presence of the carbamate functionality. Placement of an isostere of valine at P1 and a 1-(phenyl mercaptotetrazole at P'1 resulted in the most active human leukocyte elastase inhibitor within this series of compounds (Ki - 3.0 x 10(-7) M).
Kato
M
M
Division of Medicinal Chemistry and Pharmaceutics, College of Pharmacy, University of Kentucky, Lexington 40536-0082.
Agha
B J
BJ
Abdul-Raheem
A K
AK
Tsuji
K
K
Banks
W R
WR
Digenis
G A
GA
D000595:Amino Acid Sequence; D000818:Animals; D002219:Carbamates / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D019272:Leukocyte Elastase; D008969:Molecular Sequence Data; D010179:Pancreas / Q000201:enzymology; D010196:Pancreatic Elastase / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship; D013552:Swine
D002219:Carbamates; D010196:Pancreatic Elastase; D019272:Leukocyte Elastase