Building on previous investigations, structural modifications to the neuronal calcium ion channel blocker MONIRO-1 and related compounds were conducted that included replacement of the amide linker with an aniline and isosteric sulfonamide moiety, and the previously used strategy of substitution of the guanidinium group with less hydrophilic amine functionalities. A comprehensive SAR study revealed a number of phenoxyaniline and sulfonamide compounds that were more potent or had similar potency for the Ca_V2.2 and Ca_V3.2 channel compared to MONIRO-1 when evaluated in a FLIPR-based intracellular calcium response assay. Cytotoxicity investigations indicated that the sulfonamide analogues were well tolerated by Cos-7 cells at dosages required to inhibit both calcium ion channels. The sulfonamide derivatives were the most promising Ca_V2.2 inhibitors developed by us to date due, possessing high stability in plasma, low toxicity (estimated therapeutic index > 10), favourable CNS MPO scores (4.0–4.4) and high potency and selectivity, thereby, making this class of compounds suitable candidates for future in vivo studies.

中文翻译：

---

苯氧基苯胺和磺酰胺类似物对 N 型钙通道的抑制

基于之前的研究，对神经元钙离子通道阻滞剂 MONIRO-1 和相关化合物进行了结构修饰，包括用苯胺和等排磺酰胺部分替换酰胺连接体，以及用更少的胍基取代先前使用的策略。亲水性胺官能团。一项全面的 SAR 研究表明，当在基于 FLIPR 的细胞内钙反应测定中进行评估时，与 MONIRO-1 相比，许多苯氧基苯胺和磺酰胺化合物对 Ca _V 2.2 和 Ca _V 3.2 通道的效力更强或具有相似的效力。细胞毒性研究表明，在抑制两个钙离子通道所需的剂量下，Cos-7 细胞对磺酰胺类似物具有良好的耐受性。磺酰胺衍生物是我们迄今为止开发的最有前途的Ca _V 2.2抑制剂，具有血浆稳定性高、毒性低（估计治疗指数> 10）、良好的CNS MPO评分（4.0-4.4）以及高效力和选择性，因此，使得此类化合物成为未来体内研究的合适候选者。