Highly selective synthetic inhibitors with regard to plasma-kallikrein activities.
The synthetic inhibitors of plasma kallikrein (PK) were found, which are called PKSI-1007, PKSI-0180 and PKSI-0527 in our laboratories. (1) The inhibitors inhibited PK competitively with D-Pro-Phe-Arg-pNA and the Ki values obtained were considerably small, 10(-6) M-10(-7) M. However, the Ki values for glandular kallikrein (GK), plasmin (PL), thrombin (TH) and factor Xa (FXa) were larger. In particular, a selectivity of PKSI-0527 towards PK was very high and the toxicity was weak (i.v. LD50 for mice is over 100 mg/kg). (2) The inhibitors were effective (a) to prevent the bradykinin formation in the kaolin-activated human plasma and the acid-treated ascites taken from the mice bearing Sarcoma 180, (b) to prolong the coagulation time by contact activation, and (c) to inhibit the enhancement of ADP-platelet aggregation by PK. The results indicated that the some PKSI-inhibitors will be much useful for the basic studies, furthermore they deem to be even promising towards the clinical application.
Okamoto
S
S
Kobe Research Projects on Thrombosis and Haemostasis, Saiseikai-Hospital, Japan.
Okamoto
U
U
Wanaka
K
K
Hijikata-Okunomiya
A
A
Bohgaki
M
M
Naito
T
T
Horie
N
N
Okada
Y
Y
D000595:Amino Acid Sequence; D000818:Animals; D001120:Arginine / Q000031:analogs & derivatives / Q000494:pharmacology; D001920:Bradykinin / Q000096:biosynthesis; D006801:Humans; D007610:Kallikreins / Q000037:antagonists & inhibitors / Q000097:blood* / Q000494:pharmacology* / Q000633:toxicity; D007700:Kinetics; D051379:Mice; D008969:Molecular Sequence Data; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology; D012510:Sarcoma 180 / Q000378:metabolism
D010975:Platelet Aggregation Inhibitors; C062278:PKSI 1007; D001120:Arginine; D007610:Kallikreins; D001920:Bradykinin