Department of Biochemistry, University of Texas Southwestern, Dallas, Texas 75390, United States.
J Med Chem. 2011 Jun 23;54(12):4109-18. doi: 10.1021/jm200132q. Epub 2011 Jun 1.
17(R),18(S)-epoxyeicosatetraenoic acid [17(R),18(S)-EETeTr], a cytochrome P450 epoxygenase metabolite of eicosapentaenoic acid (EPA), exerts negative chronotropic effects and protects neonatal rat cardiomyocytes against Ca(2+)-overload with EC(50) ≈ 1-2 nM. Structure-activity studies revealed that a cis-Δ(11,12)- or Δ(14,15)-olefin and a 17(R),18(S)-epoxide are minimal structural elements for antiarrhythmic activity whereas antagonist activity was often associated with the combination of a Δ(14,15)-olefin and a 17(S),18(R)-epoxide. Compared with natural material, the agonist and antagonist analogues are chemically and metabolically more robust and several show promise as templates for future development of clinical candidates.
17(R),18(S)-环氧二十碳四烯酸[17(R),18(S)-EETeTr]是二十碳五烯酸 (EPA) 的细胞色素 P450 环氧化酶代谢物，具有负性变时作用，并以 EC50≈1-2 nM 的浓度保护新生大鼠心肌细胞免受 Ca(2+)-超负荷。结构活性研究表明，顺式Δ(11,12)-或Δ(14,15)-烯烃和 17(R),18(S)-环氧化物是抗心律失常活性的最小结构要素，而拮抗剂活性通常与Δ(14,15)-烯烃和 17(S),18(R)-环氧化物的组合有关。与天然物质相比，激动剂和拮抗剂类似物在化学和代谢上更稳定，并且有几个作为未来临床候选物开发模板的前景。
