Effect of a highly selective plasma-kallikrein synthetic inhibitor on contact activation relating to kinin generation, coagulation and fibrinolysis.
A highly selective inhibitor of plasma-kallikrein (PK), N-(trans-4-aminomethylcyclohexylcarbonyl)-L-phenylalanine 4-carboxymethyl-anilide hydrochloride, was designed and synthesized by the authors' group, called PKSI-527 in our laboratories. (I) PKSI-527 inhibited PK with a Ki value of 0.81 microM. By contrast, the Ki values for glandular kallikrein (GK), plasmin, thrombin, urokinase and factor Xa were greater than 500 microM, 390 microM, greater than 500 microM, 200 microM and greater than 500 microM, respectively. (II) Effects of PKSI-527 on bradykinin (BK) generation, coagulation and fibrinolysis by contact activation were examined using human plasma. (a) BK generation induced by kaolin appeared to be reduced by PKSI-527. Furthermore BK generation induced by lambda-carrageenan, a strong inflammatory agent, was also reduced by PKSI-527. (b) Partial thromboplastin time (PTT) was prolonged by PKSI-527, indicating the suppression of the intrinsic coagulation system. (c) Euglobulin clot lysis time (ECLT) of plasma which was shortened by activation with kaolin, was prolonged by the addition of PKSI-527, confirming the participation of PK in contact-fibrinolysis. These results indicate that PKSI-527 shows great potential in elucidating the significance of PK, and as such deserves further investigation.
Wanaka
K
K
Kobe Research Projects on Thrombosis and Haemostasis, Saiseikai-Hospital, Japan.
Okamoto
S
S
Bohgaki
M
M
Hijikata-Okunomiya
A
A
Naito
T
T
Okada
Y
Y
D001777:Blood Coagulation / Q000187:drug effects*; D001920:Bradykinin / Q000096:biosynthesis*; D002351:Carrageenan / Q000494:pharmacology; D003509:Cyclohexanecarboxylic Acids / Q000494:pharmacology*; D005342:Fibrinolysis / Q000187:drug effects*; D006801:Humans; D007610:Kallikreins / Q000037:antagonists & inhibitors*; D007616:Kaolin / Q000494:pharmacology; D007700:Kinetics; D010649:Phenylalanine / Q000031:analogs & derivatives* / Q000494:pharmacology; D014148:Tranexamic Acid / Q000031:analogs & derivatives / Q000494:pharmacology*
D003509:Cyclohexanecarboxylic Acids; C064866:PKSI 527; D007616:Kaolin; D010649:Phenylalanine; D014148:Tranexamic Acid; D002351:Carrageenan; D007610:Kallikreins; D001920:Bradykinin