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Biomedical subjects

K Wanaka

Publications and source records attributed to K Wanaka.

30 records · Page 2Linked to original sources
PubMed1993

Development of active center-directed plasmin and plasma kallikrein inhibitors and studies on the structure-inhibitory activity relationship.

The molecule of trans-4-aminomethylcyclohexanecarbonylphenylalanine 4-carboxymethylanilide (8), which is a potent and selective inhibitor of plasma kallikrein, can be divided into three parts (P1, P1' and P2'), each of which contains one of the rings. In order to study the role of each part in the manifestation of potent and selective inhibitory activity and the relationship between the structure and inhibitory activities toward plasmin, plasma kallikrein, urokinase and thrombin, each part was substituted with various other moieties to give many kinds of analogs and their inhibitory activities against the above enzymes were examined. Among them, trans-4-aminomethylcyclohexanecarbonyl-O-2-bromobenzyloxycarbon yltyrosine 4-acetylanilide (12) inhibited plasmin and plasma kallikrein with IC50 values of 2.3 x 10(-7) M and 3.7 x 10(-7) M, and K(i) values of 1.2 x 10(-7) M and 1.3 x 10(-7) M, respectively.

Amino Acid Sequence↗
PubMed1992

A finding of highly selective synthetic inhibitor of plasma kallikrein; its action to bradykinin generation, intrinsic coagulation and experimental DIC.

We found a novel and highly selective synthetic inhibitor of plasma kallikrein (PK), called PKSI-527; the Ki value was 0.81 microM. PKSI-527 inhibited the bradykinin (BK) generation induced by kaolin and prolonged partial thromboplastin time (PTT). PKSI-527 prevented the decrease of fibrinogen (Fg) levels due to i.v. injection of ellagic acid in mice and ameliorated the endotoxin (ET)-induced DIC in rats.

Animals↗
PubMed1992

Synthesis of trans-4-aminomethylcyclohexanecarbonyl-L- and -D-phenylalanine-4-carboxymethylanilide and examination of their inhibitory activity against plasma kallikrein.

Based on studies of structure-activity relationship, trans-4-aminomethylcyclohexanecarbonyl-L-phenylalanine-4-carbox ymethylanilide (Tra-Phe-APAA) was designed as a selective plasma kallikrein inhibitor and synthesized. Tra-Phe-APAA inhibited plasma kallikrein with a Ki value of 0.81 microM, while it inhibited glandular kallikrein, plasmin, urokinase, factor Xa and thrombin with Ki values of greater than 500, 390, 200, greater than 500, and greater than 500 microM, respectively. However, its stereoisomer, Tra-D-Phe-APPA did not exhibit any detectable inhibitory activity against the above enzymes.

Animals↗
PubMed1991

Development of active center-directed inhibitors against plasmin.

Active center-directed inhibitors of plasmin were designed based on the structure of specific substrates of plasmin and then synthesized. Their effects on plasmin were examined and the structure-inhibitory activity relationship was studied. N alpha-trans-4-Aminomethylcyclohexanecarbonyllysine 4-benzoylanilide (Tra-Lys-BZA) inhibited plasmin activities toward S-2251 and fibrin with IC50 values of 15 and 6.1 microM, respectively and N alpha-trans-4-aminomethylcyclohexane-carbonyllysine 4-benzylpiperidine amide (Tra-Lys-BPP) did not show any detectable inhibitory activity. Moreover, it was revealed that Tra-Lys-4-methoxycarbonylanilide inhibited plasma kallikrein more potently than plasmin.

Binding Sites↗
PubMed1991

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).

Amino Acid Sequence↗
PubMed1990

Effect of a synthetic thrombin-inhibitor MD805 on the reaction between thrombin and plasma antithrombin-III.

MD805, a synthetic thrombin-inhibitor, effectively retarded the time-dependent inactivation of thrombin which was generated endogeneously or added exogeneously in human plasma. The kinetical study of the time-dependent inactivation indicated that the type of inhibition was competitive and the obtained Ki of MD805 for thrombin was 3 x 10(-8)M. MD805 also inhibited the formation of thrombin-ATIII complex. These results indicated that the active site of thrombin was involved in the reaction between thrombin and ATIII, and that MD805 competed with ATIII for thrombin in exactly the same manner as it competed with fibrinogen or synthetic peptide substrates. As a result, MD805 would serve as a protective agent for ATIII from being consumed, in addition to its potent thrombin-inhibitory activity without the aid of ATIII. By contrast, heparin accelerated the time-dependent inactivation rate of thrombin and the formation of thrombin-ATIII complex, which indicates that heparin accelerates the consumption of ATIII.

Antithrombin III↗
PubMed1990

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.

Blood Coagulation↗
PubMed1989

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.

Amino Acid Sequence↗
PubMed1989

Synthesis of tripeptide chloromethyl ketones and examination of their inhibitory effects on plasmin and plasma kallikrein.

With the aim of obtaining selective synthetic inhibitors of plasmin and plasma kallikrein, D-Ile-Phe-Lys-CH2Cl, Ile-Phe-Lys-CH2Cl, D-Ile-Phe-Arg-CH2Cl and Ile-Phe-Arg-CH2Cl were synthesized and their inhibitory activity against plasmin, plasma kallikrein and other trypsin-like serine proteinases was examined. Among them, D-Ile-Phe-Arg-CH2Cl exhibited a highly selective inhibitory activity against plasma kallikrein, yet D-Ile-Phe-Lys-CH2Cl exhibited nearly the same order of inhibitory activity against plasmin as well as plasma kallikrein.

Amino Acid Chloromethyl Ketones↗
PubMed1986

Synthesis of plasmin substrates and relationship between their structure and plasmin activity.

The plasmin substrates, D-Ile-Phe-Lys-pNA (I), 3-MV-Phe-Lys-pNA (II), Ile-Phe-Lys-pNA (III), D-Pro-Phe-Lys-pNA (IV), CP-Phe-Lys-pNA (V) and Pro-Phe-Lys-pNA (VI), were synthesized by the conventional solution method and the kinetic parameters of their amidolysis by plasmin were determined. It was found that the free amino group of the D-amino acid in substrates (I) and (IV) made a contribution to an increment in affinity between the substrate and plasmin.

Chemical Phenomena↗