Development of selective inhibitors against plasma kallikrein.
Specific plasma kallikrein inhibitors were designed and synthesized and their structure-activity relationship was studied. trans-4-Aminomethylcyclohexanecarbonyl (Tra)-lysyl-4-ethoxycarbonylanilide inhibited plasma kallikrein and plasmin with IC50 values of 23 and 210 microM, respectively, indicating that this compound is fairly specific to plasma kallikrein. Tra-arginyl-4-ethoxycarbonylanilide inhibited plasma kallikrein and plasmin with IC50 values of 16 and 480 microM, respectively. Tra-homoarginyl-4-carboxyanilide inhibited plasma kallikrein and plasmin with IC50 values of 14 microM and 1 mM, respectively. Finally, Tra-Arg(Mts)-4-acetylanilide (ACA) exhibited potent and selective inhibitory activity against plasma kallikrein (IC50 value for plasma kallikrein: 2 microM and for plasmin: 42 microM).
Teno
N
N
Faculty of Pharmaceutical Sciences, Kobe-Gakuin University, Japan.
Wanaka
K
K
Okada
Y
Y
Tsuda
Y
Y
Okamoto
U
U
Hijikata-Okunomiya
A
A
Naito
T
T
Okamoto
S
S
D000595:Amino Acid Sequence; D005341:Fibrinolysin / Q000037:antagonists & inhibitors; D006801:Humans; D066298:In Vitro Techniques; D007610:Kallikreins / Q000037:antagonists & inhibitors* / Q000097:blood; D008969:Molecular Sequence Data; D013917:Thrombin / Q000037:antagonists & inhibitors
D007610:Kallikreins; D013917:Thrombin; D005341:Fibrinolysin