Development of potent and selective plasmin and plasma kallikrein inhibitors and studies on the structure-activity relationship.
Based on structure-activity relationship studies, we designed and synthesized plasmin (PL) and plasma kallikrein (PK) inhibitors. Trans-(4-aminomethylcyclohexanecarbonyl)-Tyr(O-Pic)-octylamide inhibited PL, PK, urokinase (UK) and thrombin (TH) with IC50 values of 0.53, 30, 5.3 and > 400 microm, respectively. Trans-(4-aminomethylcyclohexanecarbonyl)-Tyr(O-2-Pyrim)-4-carboxyanilide inhibited PL, PK, UK and TH with IC50 values of 36, 0.56, 440 and > 1,000 microM, respectively.
Okada
Y
Y
Faculty of Pharmaceutical Sciences, Kobe Gakuin University, Japan. okada@pharm.kobegakuin.ac.jp
Tsuda
Y
Y
Tada
M
M
Wanaka
K
K
Okamoto
U
U
Hijikata-Okunomiya
A
A
Okamoto
S
S
D000933:Antifibrinolytic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D005341:Fibrinolysin / Q000037:antagonists & inhibitors; D006801:Humans; D020128:Inhibitory Concentration 50; D020842:Plasma Kallikrein / Q000037:antagonists & inhibitors*; D011480:Protease Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship; D013917:Thrombin / Q000037:antagonists & inhibitors; D014568:Urokinase-Type Plasminogen Activator / Q000037:antagonists & inhibitors
D000933:Antifibrinolytic Agents; D011480:Protease Inhibitors; D020842:Plasma Kallikrein; D013917:Thrombin; D005341:Fibrinolysin; D014568:Urokinase-Type Plasminogen Activator