In this Letter we describe structure–activity relationship (SAR) studies conducted in five distinct regions of a new 2-amino-N-phenylacetamides series of Slack potassium channel inhibitors exemplified by recently disclosed high-throughput screening (HTS) hit VU0606170 (4). New analogs were screened in a thallium (Tl⁺) flux assay in HEK-293 cells stably expressing wild-type human (WT) Slack. Selected analogs were screened in Tl⁺ flux versus A934T Slack and other Slo family members Slick and Maxi-K and evaluated in whole-cell electrophysiology (EP) assays using an automated patch clamp system. Results revealed the series to have flat SAR with significant structural modifications resulting in a loss of Slack activity. More minor changes led to compounds with Slack activity and Slo family selectivity similar to the HTS hit.

在这封信中，我们描述了在新型 2-氨基-N-苯基乙酰胺系列 Slack 钾通道抑制剂的五个不同区域进行的构效关系 (SAR) 研究，例如最近披露的高通量筛选 (HTS) 命中 VU0606170 ( 4 ) 。在稳定表达野生型人 (WT) Slack 的 HEK-293 细胞中通过铊 (Tl ⁺ ) 通量测定筛选新的类似物。^{选定的类似物在 Tl +} Flux 中与 A934T Slack 和其他 Slo 家族成员 Slick 和 Maxi-K进行筛选，并使用自动膜片钳系统在全细胞电生理学 (EP) 测定中进行评估。结果显示，该系列的 SAR 较平坦，且结构发生重大修改，导致 Slack 活动损失。更小的变化导致化合物具有与 HTS 命中相似的 Slack 活性和 Slo 家族选择性。