Pharmacokinetic/Pharmacodynamic Assessment of the Structural Refinement of Clopidogrel Focusing on the Balance between Bioactivation and Deactivation.

IF 4.4 3区 医学 Q1 PHARMACOLOGY & PHARMACY
Dong Sun, Yingze Liu, Lin Zhu, Zhiping Xu, Yuyao Zhang, Haipeng Li, Huan Yang, Xia Cao, Jingkai Gu
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引用次数: 0

Abstract

The delicate balance between ischemic and bleeding risks is a critical factor in antiplatelet therapy administration. Clopidogrel and prasugrel, belonging to the thienopyridine class of antiplatelet drugs, are known for their variability in individual responsiveness and high incidence of bleeding events, respectively. The present study is centered on the development and assessment of a range of deuterated thienopyridine derivatives, leveraging insights from structure-pharmacokinetic relationships of clopidogrel and prasugrel. Our approaches were grounded in the molecular framework of clopidogrel and incorporated the C2-pharmacophore design from prasugrel. The selection of ester or carbamate substituents at the C2-position facilitated the generation of the 2-oxointermediate through hydrolysis, akin to prasugrel, thereby bypassing the issue of CYP2C19 dependency. The bulky C2-pharmacophore in our approach distinguishes itself from prasugrel's acetyloxy substituent by exhibiting a moderated hydrolysis rate, resulting in a more gradual formation of the active metabolite. Excessive and rapid release of the active metabolite, believed to be linked with an elevated risk of bleeding, is thus mitigated. Our proposed structural modification retains the hydrolysis-sensitive methyl ester of clopidogrel but substitutes it with a deuterated methyl group, shown to effectively reduce metabolic deactivation. Three promising compounds demonstrated a pharmacokinetic profile similar to that of clopidogrel at four times the dose, while also augmenting its antiplatelet activity. SIGNIFICANCE STATEMENT: Inspired by the structure-pharmacokinetic relationship of clopidogrel and prasugrel, a range of clopidogrel derivatives were designed, synthesized, and assessed. Among them, three promising compounds have been identified, striking a delicate balance between efficacy and safety for antiplatelet therapy. Additionally, the ozagrel prodrug conjugate was discovered to exert a synergistic therapeutic effect alongside clopidogrel.

对氯吡格雷结构改进的药代动力学/药效学评估,重点是生物活化和去活化之间的平衡。
缺血和出血风险之间的微妙平衡是抗血小板疗法的一个重要考虑因素。氯吡格雷和普拉格雷都属于噻吩吡啶类抗血小板药物,但这两种药物分别具有个体反应性多变和出血事件较多的特点。目前的研究重点是评估一系列氚代氯吡格雷衍生物的药代动力学和药效学,充分利用在开发噻吩吡啶类药物过程中从结构-药代动力学关系中获得的见解。我们的方法以氯吡格雷的分子骨架为基础,并采用了普拉格雷的 C2-药代体设计。所选的 C2-药代体与普拉格雷的乙酰氧基取代基不同,它的水解速度较慢,因此形成的活性代谢物较温和。因此,应避免活性代谢物的过度和突然释放,因为据信这与出血风险的增加有关。我们建议的结构改造保留了氯吡格雷对水解敏感的甲酯,但用一个氚代甲基取代,这已被证明能有效减少代谢失活。对氯吡格雷衍生物的评估主要基于与活性代谢物暴露相关的标准。与氯吡格雷相比,三种前景看好的化合物表现出更高的生物转化效率、相似的Cmax、延迟的Tmax、更强的抗血小板活性以及更低的出血风险,且给药剂量导致活性代谢物的暴露量相似。意义声明 评估了一系列新设计的氯吡格雷衍生物的药代动力学和药效学,以验证其结构改造的合理性。三个有前景的化合物显示出平衡的药代动力学,其特点是失活速度比氯吡格雷慢,生物活化速度比普拉格雷慢。与氯吡格雷相比,这些化合物在暴露于类似活性代谢物的情况下,抗血小板活性增强,出血风险降低。研究发现,D3-氯吡格雷-奥扎格雷共轭物具有协同治疗效果。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
CiteScore
6.50
自引率
12.80%
发文量
128
审稿时长
3 months
期刊介绍: An important reference for all pharmacology and toxicology departments, DMD is also a valuable resource for medicinal chemists involved in drug design and biochemists with an interest in drug metabolism, expression of drug metabolizing enzymes, and regulation of drug metabolizing enzyme gene expression. Articles provide experimental results from in vitro and in vivo systems that bring you significant and original information on metabolism and disposition of endogenous and exogenous compounds, including pharmacologic agents and environmental chemicals.
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