Delving into the Latest Updates on FK-633 with Synapse

Overview

Basic Info

Drug Type

Small molecule drug

Synonyms

FK633, FR 144633, FR-144633

Target

GP IIb/IIIa

Action

antagonists

Mechanism

GP IIb/IIIa antagonists(Integrin alpha-IIb/beta-3 antagonists)

Therapeutic Areas

Cardiovascular Diseases

Active Indication-

Inactive Indication

Coronary RestenosisThrombosis

Originator Organization

Astellas Pharma, Inc.

Active Organization-

Inactive Organization

Astellas Pharma, Inc.Fujisawa Pharmaceutical Co., Ltd.

License Organization-

Drug Highest PhaseDiscontinuedPhase 2

First Approval Date-

Regulation-

Login to view timeline

Structure/Sequence

Molecular FormulaC20H28N4O7

InChIKeyJFCXCBBSUORTNS-YOEHRIQHSA-N

CAS Registry147865-49-4

New in vitro methods are desirable for the analysis of platelet aggregation and screening novel anti-platelet agents using whole blood. To this end, we examined platelet aggregation and thrombus formation in whole human blood from healthy volunteers using a microchannel array flow analyzer (MC-FAN). Platelet aggregation in whole blood, treated with the activating agents ADP, collagen or ristocetin was detected in the MC-FAN by measuring the decrease in flow rate as a function of agent concentration. The results were compared with aggregation in platelet rich plasma (PRP) in a conventional aggregometer, as measured by the increase in optical density. The MC-FAN detected platelet aggregation in whole blood at two- to four-fold lower concentrations of agonist compared to those in PRP in the aggregometer. Anti-platelet agents attenuated the decrease in blood flow rate in the MC-FAN by inhibiting fibrin formation and platelet aggregation, but anticoagulants only inhibited fibrin formation and did not affect blood flow rates. These findings suggest that the MC-FAN system may be a useful method for the evaluation of platelet activation and facilitate the development of novel anti-platelet agents.

01 Jan 2008·Thrombosis researchQ3 · MEDICINE

Platelet anaesthesia during extracorporeal circulation: Differential effects of GP IIb/IIIa blockers on platelet activation marker P-selectin expression at hypothermia

Q3 · MEDICINE

Article

Author: Wendel, Hans Peter ; Straub, Andreas ; Ziemer, Gerhard ; Azevedo, Ruben ; Schiebold, Daniela ; Dietz, Klaus

INTRODUCTION:

Blood contact with artificial surfaces of extracorporeal circulation (ECC) and hypothermia as applied in cardiac surgery cause platelet dysfunction possibly followed by bleeding complications. "Platelet anaesthesia" is a pharmacological strategy to protect platelets against ECC-induced damage using a GP IIb/IIIa blocker, which should be short acting to achieve maximal therapy control thereby avoiding post-ECC haemorrhage. However, GP IIb/IIIa blockers can paradoxically induce platelet activation, which may limit their efficiency as anti-platelet drugs. This in-vitro study investigated potentially platelet-activating effects of short-acting GP IIb/IIIa blockers during normothermic and hypothermic ECC.

MATERIALS AND METHODS:

Control (untreated) and treated (using either FK633 [half-life: 0.52 h], tirofiban [half-life: 1.5-2 h], or eptifibatide [half-life: 1.5 h]) heparinized blood was circulated in an ECC-model at normothermia (37 degrees C) and hypothermia (18 degrees C). Percentages of platelet aggregates and P-selectin-expressing (activated) platelets, platelet-counts and Thrombin-Antithrombin (TAT) complex formation were determined before (baseline) and after ECC. Statistical analysis was performed using multifactorial ANOVA after log-transforming the data.

RESULTS:

GP IIb/IIIa blockade inhibited ECC-induced platelet aggregation and platelet loss and decreased P-selectin expression at normothermia. During hypothermic ECC P-selectin was decreased by tirofiban but augmented by FK633 and eptifibatide. TAT formation was only decreased by FK633.

CONCLUSIONS:

Especially regarding its ultra-short half-life FK633 has the best properties for platelet protection during normothermic ECC. However, at hypothermia FK633 and eptifibatide induce platelet activation. In relation with "platelet anaesthesia" possible hypothermia-associated prothrombotic side effects of GP IIb/IIIa blockers should be considered.

01 Oct 2005·Journal of thrombosis and haemostasis : JTHQ2 · MEDICINE

Association of the antagonism of von Willebrand factor but not fibrinogen by platelet αIIbβ3 antagonists with prolongation of bleeding time

Q2 · MEDICINE

Article

Author: Aoki, T. ; Yamanaka, T. ; Honda, S. ; Mutoh, S. ; Mihara, K. ; Okubo, M. ; Tomiyama, Y. ; Moriguchi, A.

BACKGROUND:

The alphaIIbbeta3 antagonists inhibit platelet aggregation and are used as antithrombotic agents for cardiothrombotic disease. The present study investigates the correlation of inhibition of fibrinogen and von Willebrand factor (VWF) binding by alphaIIbbeta3 antagonists with the inhibition of platelet aggregation and prolongation of bleeding time (BT).

METHODS:

Inhibition of fibrinogen and VWF binding were assessed in a purified alphaIIbbeta3-binding assay. As an in vitro cell-based assay, platelet aggregation and VWF-mediated adhesion studies were performed using human platelets. In vivo effects on BT were measured using a template device in dogs at the same time as an ex vivo aggregation study was performed.

RESULTS:

In vitro studies demonstrated that the antiaggregatory effects of alphaIIbbeta3 antagonists correlate with their inhibition of fibrinogen binding, but not VWF. Interestingly, the effects of alphaIIbbeta3 antagonists on BT could be differentiated from the inhibition of platelet aggregation. Furthermore, this differentiation was strongly correlated with the different inhibitory potencies between fibrinogen and VWF binding, as well as that between VWF-mediated adhesion and aggregation.

CONCLUSIONS:

Our study provides novel evidence showing that the inhibitory effect of alphaIIbbeta3 antagonists on VWF, but not fibrinogen binding, correlates with their ability to prolong BT.

100 Deals associated with FK-633

Login to view more data