Selective nitrile inhibitors to modulate the proteolytic synergism of cathepsins S and F.
A series of dipeptide nitriles with different P3 substituents was designed to explore the S3 binding pocket of cathepsin S. Racemic 7-16 and the enantiopure derivative (R)-22 proved to be potent inhibitors of human cathepsin S and exhibited notable selectivity over human cathepsins L, K, and B. Inhibition of cathepsin F, the functional synergist of cathepsin S, was not observed. The azadipeptide analogue of 22, compound 26, was highly potent but nonselective.
Pharmaceutical Institute, Pharmaceutical Chemistry I, University of Bonn, An der Immenburg 4, D-53121 Bonn, Germany.
Maxim
M
Frizler
Janina
J
Schmitz
Anna-Christina
AC
Schulz-Fincke
Michael
M
Gütschow
D056646:Cathepsin F / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D002403:Cathepsins / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D004151:Dipeptides / Q000737:chemistry; D006801:Humans; D020128:Inhibitory Concentration 50; D007700:Kinetics; D009570:Nitriles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D011480:Protease Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D059748:Proteolysis / Q000187:drug effects*; D013379:Substrate Specificity
D004151:Dipeptides; D009570:Nitriles; D011480:Protease Inhibitors; D002403:Cathepsins; C028217:cathepsin S; D056646:Cathepsin F