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Antiplatelet activity of BRX-018, (6aS,cis)-malonic acid 3-acetoxy-6a9-bis-(2-methoxycarbonyl-acetoxy)-6,6a,7,11b-tetrahydro-indeno[2,1-c]chromen-10-yl ester methylester.

Lee, GY; Chang, TS; Lee, KS; Khil, LY; Kim, D; Chung, JH; Kim, YC; Lee, BH; Moon, CH; Moon, CK
Thrombosis research, 115(4):309-318, 2005
Journal Title
Thrombosis research
Brazilin (7,11b-dihydrobenz[b]indeno[1,2-d]pyran-3,6a,9,10 (6H)-tetrol), the major component of Caesalpinia sappan L., was reported to show antiplatelet activity through the inhibition of phospholipase A2 (PLA2) activity and the increase in intracellular free Ca2+ concentration ([Ca2+]i). To search more potential antiplatelet agent, brazilin derivatives were synthesized and examined for their effects on the platelet aggregation. Among those compounds, BRX-018, (6aS,cis)-Malonic acid 3-acetoxy-6a9-bis-(2-methoxycarbonyl-acetoxy)-6,6a,7,11b-tetrahydro-indeno[2,1-c]chromen-10-yl ester methylester, was confirmed as one of the potential antiplatelet agents. In the present study, we investigated the antiplatelet mechanism of BRX-018. BRX-018 inhibited the thrombin-, collagen-, and ADP-induced rat platelet aggregation in a concentration-dependent manner, with IC50 values of 35, 15, and 25 microM, respectively. BRX-018 also inhibited thrombin-induced dense granule secretion, thromboxane A2 (TXA2) synthesis, and [Ca2+]i elevation in platelets. BRX-018 was also found to inhibit A23187-induced [Ca2+]i and aggregation in the presence of apyrase (ADP scavenger) but not in the presence of both apyrase and indomethacin (a specific inhibitor of cyclooxygenase, COX). Although BRX-018 significantly inhibited arachidonic acid (AA)-induced aggregation and TXA2 synthesis, it had no significant inhibitory effect on cyclooxygenase activity in vitro. In contrast, BRX-018 inhibited the activity of purified PLA2. Dixon plot showed that this inhibition was mixed type with an inhibition constant of Ki=23 microM. Taken together, the present study suggests that BRX-018 may be a promising antiplatelet agent and that its antiplatelet activity may be based on the inhibitory mechanisms on TXA2 synthesis in stimulated platelets.
MeSH terms
Adenosine Diphosphate/pharmacologyAnimalsArachidonic Acid/pharmacologyBenzopyrans/chemical synthesisBenzopyrans/chemistryBenzopyrans/pharmacology*Blood Platelets/drug effectsBlood Platelets/physiologyCalcimycin/pharmacologyCalcium/bloodCattleCell Degranulation/drug effectsCollagen/pharmacologyIonophores/pharmacologyMaleMalonates/chemical synthesisMalonates/chemistryMalonates/pharmacology*Phospholipases A/antagonists & inhibitorsPhospholipases A2Platelet Aggregation Inhibitors/chemical synthesisPlatelet Aggregation Inhibitors/chemistryPlatelet Aggregation Inhibitors/pharmacology*Prostaglandin-Endoperoxide Synthases/bloodRatsRats, Sprague-DawleySwineThrombin/pharmacologyThromboxane B2/blood
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Journal Papers > School of Medicine / Graduate School of Medicine > Physiology
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