New highly active antiplatelet agents with dual specificity for platelet P2Y1 and P2Y12 adenosine diphosphate receptors

被引：37

作者：

Yanachkov, Ivan B. ^{[1
]}

Chang, Hung ^{[3
,4
]}

Yanachkova, Milka I. ^{[1
]}

Dix, Edward J. ^{[1
]}

Berny-Lang, Michelle A. ^{[2
]}

Gremmel, Thomas ^{[2
]}

Michelson, Alan D. ^{[2
,3
]}

Wright, George E. ^{[1
]}

Frelinger, Andrew L., III ^{[2
,3
]}

机构：

[1] GLSynthesis Inc, Worcester, MA 01605 USA

[2] Harvard Univ, Sch Med, Dana Farber Canc Inst, Ctr Platelet Res Studies,Div Hematol Oncol,Boston, Boston, MA 02115 USA

[3] Univ Massachusetts, Sch Med, Dept Pediat, Ctr Platelet Funct Studies, Worcester, MA USA

[4] Chang Gung Univ, Div Hematol, Chang Gung Mem Hosp, Taipei, Taiwan

来源：

EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY | 2016年 / 107卷

关键词：

Antiplatelet therapy; Antithrombotics; Adenosine diphosphate; Cardiovascular disease; Acute coronary syndromes; P2Y(1); P2Y(12); P2X1; Dinucleoside polyphosphates; Bis-nucleoside polyphosphates; Inhibitors; Platelets; DEOXYADENOSINE BISPHOSPHATE DERIVATIVES; NUCLEOTIDE P2 RECEPTORS; ACID RELATED-COMPOUNDS; CARDIOVASCULAR-DISEASE; MOLECULAR RECOGNITION; DIADENOSINE POLYPHOSPHATES; POTENT ANTAGONISTS; P2X(1) RECEPTORS; SIGNAL MOLECULES; ACTIVATION;

D O I：

10.1016/j.ejmech.2015.10.055

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Currently approved platelet adenosine diphosphate (ADP) receptor antagonists target only the platelet P2Y(12) receptor. Moreover, especially in patients with acute coronary syndromes, there is a strong need for rapidly acting and reversible antiplatelet agents in order to minimize the risk of thrombotic events and bleeding complications. In this study, a series of new P-1,P-4-di(adenosine-5') tetraphosphate (Ap(4)A) derivatives with modifications in the base and in the tetraphosphate chain were synthesized and evaluated with respect to their effects on platelet aggregation and function of the platelet P2Y(1), P2Y(12), and P2X1 receptors. The resulting structure activity relationships were used to design Ap(4)A analogs which inhibit human platelet aggregation by simultaneously antagonizing both P2Y(1) and P2Y(12) platelet receptors. Unlike Ap(4)A, the analogs do not activate platelet P2X1 receptors. Furthermore, the new compounds exhibit fast onset and offset of action and are significantly more stable than Ap(4)A to degradation in plasma, thus presenting a new promising class of antiplatelet agents. (C) 2015 Elsevier Masson SAS. All rights reserved.

引用

页码：204 / 218

页数：15

共 64 条

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