Design, Synthesis and Pharmacokinetic Study of Deuterated Ticagrelor Derivatives,ChemistrySelect

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Design, Synthesis and Pharmacokinetic Study of Deuterated Ticagrelor Derivatives
ChemistrySelect ( IF 1.9 ) Pub Date : 2020-09-16 , DOI: 10.1002/slct.202002605
Jing Chen ₁ , Siyu Wang ₂ , Jianjun Zhang ₃ , Huazhou Ying ₂ , Hao Zheng ₄ , Xiaowu Dong ₂ , Jinxin Che ₂ , Xin Chen ₄ , Gang Cheng ₁

Affiliation

Ticagrelor is the first reversible P2Y₁₂ receptor antagonist that inhibits ADP‐induced platelet aggregation. In several areas of biomedical research, the deuterium strategy has been employed to slow down the rate of drug metabolism and improve the pharmacokinetic properties of drugs. In the present study, several deuterated analogs of ticagrelor, as well as their prodrugs, were designed and synthesized in order to improve the metabolic stability of ticagrelor. Further in vitro and in vivo pharmacokinetic experiments using the deuterated derivates 24 and 25 demonstrated that the metabolic stability of deuterated compounds was improved compared to that of the parent compound. In addition, the half‐life of the deuterated valine ester prodrug 31 (t_1/2 =2.54±0.32 h) was significantly lengthened, reaching a value of approximately 40 % longer than that of ticagrelor (t_1/2=1.77±0.14 h).

中文翻译：

氘代替卡格雷洛衍生物的设计，合成和药代动力学研究

替卡格雷是第一个可逆的P2Y ₁₂受体拮抗剂，可抑制ADP诱导的血小板凝集。在生物医学研究的几个领域，氘策略已被用于减慢药物代谢速率并改善药物的药代动力学特性。在本研究中，设计和合成了几种替卡格雷的氘代类似物及其前药，以提高替卡格雷的代谢稳定性。使用氘代衍生物24和25的进一步体外和体内药代动力学实验表明，与母体化合物相比，氘代化合物的代谢稳定性得到了改善。此外，氘代缬氨酸酯前药31的半衰期（t _1/2 = 2.54±0.32 h）显着延长，其值比替卡格雷（t _1/2 = 1.77±0.14 h）长约40％。

更新日期：2020-09-16

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