Cardiovascular diseases (CVDs) present high prevalence rates in the current world. It is estimated that approximately one-third of the global deaths are related to CVDs, and thus there is still a need for novel drugs to treat these disorders. We serendipitously discovered that LINS01005 (5a) is a potent vasodilating agent in rat aorta, and therefore a set of analogues were evaluated for the vasodilating potency in Wistar and SHR rat thoracic aorta precontracted with norepinephrine, with endothelium intact (E+) or denuded (E-) aortic rings. Compounds 5a and 5b were the most potent, showing submicromolar potency for endothelium intact vessels (EC50 853 and 941 nM, respectively) and micromolar values for E- vessels (EC50 2.4 and 7.1 µM, respectively). These compounds were indeed significantly more potent vasodilating agents in SHR-derived aortic rings (p < 0.001), showing nanomolar potency for 5a [EC50 2.4 nM (E+) 9.0 nM (E-)] and 5b [EC50 20 nM (E+) 2.1 µM (E-)]. SAR analysis though PCA and HCA were performed, suggesting that N-phenylpiperazine is essential to the activity, while increasing volume in the substituted aromatic moiety is detrimental to the potency. This is the first report of the vasodilating properties of such compounds, and studies regarding the mechanism of action are in progress in our group.

中文翻译：

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新型有效的血管舒张药：评估LINS01005及其衍生物在大鼠主动脉中的活性和效能。

心血管疾病（CVD）在当前世界中具有很高的患病率。据估计，全球死亡人数中约有三分之一与CVD相关，因此仍然需要用于治疗这些疾病的新型药物。我们偶然发现LINS01005（5a）是大鼠主动脉中的一种有效血管舒张剂，因此评估了一组类似物在预配去甲肾上腺素，内皮完整（E +）或裸露（E）的Wistar和SHR大鼠胸主动脉中的血管舒张功效。 -）主动脉环。化合物5a和5b最有效，对内皮完整血管显示亚微摩尔效价（分别为EC50 853和941 nM）和E血管的微摩尔值（分别为EC50 2.4和7.1 µM）。这些化合物在SHR衍生的主动脉环中确实是更有效的血管舒张剂（p <0.001），显示5a [EC50 2.4 nM（E +）9.0 nM（E-）]和5b [EC50 20 nM（E +）2.1]的纳摩尔浓度。 µM（E-）]。通过PCA和HCA进行的SAR分析表明，N-苯基哌嗪对活性至关重要，而增加的取代芳族化合物的体积则不利于效能。这是此类化合物血管舒张特性的首次报道，有关作用机理的研究正在进行中。而增加取代的芳族部分中的体积不利于效力。这是此类化合物血管舒张特性的首次报道，有关作用机理的研究正在进行中。而增加取代的芳族部分中的体积不利于效力。这是此类化合物血管舒张特性的首次报道，有关作用机理的研究正在进行中。