PDF(Pubmed)
Abstract：
Vascular smooth muscle KATP channels critically regulate blood flow and blood pressure by modulating vascular tone and therefore represent attractive drug targets for treating several cardiovascular disorders. However, the lack of potent inhibitors that can selectively inhibit Kir6.1/SUR2B (vascular KATP) over Kir6.2/SUR1 (pancreatic KATP) has eluded discovery despite decades of intensive research. We therefore screened 47,872 chemically diverse compounds for novel inhibitors of heterologously expressed Kir6.1/SUR2B channels. The most potent inhibitor identified in the screen was an N-aryl-N\'-benzyl urea compound termed VU0542270. VU0542270 inhibits Kir6.1/SUR2B with an IC50 of approximately 100 nM but has no apparent activity toward Kir6.2/SUR1 or several other members of the Kir channel family at doses up to 30 µM (>300-fold selectivity). By expressing different combinations of Kir6.1 or Kir6.2 with SUR1, SUR2A, or SUR2B, the VU0542270 binding site was localized to SUR2. Initial structure-activity relationship exploration around VU0542270 revealed basic texture related to structural elements that are required for Kir6.1/SUR2B inhibition. Analysis of the pharmacokinetic properties of VU0542270 showed that it has a short in vivo half-life due to extensive metabolism. In pressure myography experiments on isolated mouse ductus arteriosus vessels, VU0542270 induced ductus arteriosus constriction in a dose-dependent manner similar to that of the nonspecific KATP channel inhibitor glibenclamide. The discovery of VU0542270 provides conceptual proof that SUR2-specific KATP channel inhibitors can be developed using a molecular target-based approach and offers hope for developing cardiovascular therapeutics targeting Kir6.1/SUR2B. SIGNIFICANCE STATEMENT: Small-molecule inhibitors of vascular smooth muscle KATP channels might represent novel therapeutics for patent ductus arteriosus, migraine headache, and sepsis; however, the lack of selective channel inhibitors has slowed progress in these therapeutic areas. Here, this study describes the discovery and characterization of the first vascular-specific KATP channel inhibitor, VU0542270.
摘要：
血管平滑肌KATP通道通过调节血管张力来调节血流量和血压，因此代表了治疗几种心血管疾病的有吸引力的药物靶标。然而,尽管进行了数十年的深入研究,但缺乏能够选择性抑制Kir6.1/SUR2B(血管KATP)而非Kir6.2/SUR1(胰腺KATP)的有效抑制剂,这暗示了这一发现.因此，我们筛选了47,872种化学上不同的化合物，用于异源表达的Kir6.1/SUR2B通道的新型抑制剂。在筛选中鉴定的最有效的抑制剂是称为VU0542270的N-芳基-N'-苄基脲化合物。VU0542270抑制Kir6.1/SUR2B，IC50约为100nM，但在高达30µM的剂量下对Kir6.2/SUR1或Kir通道家族的其他成员没有明显活性（>300倍选择性）。通过表达Kir6.1或Kir6.2与SUR1，SUR2A的不同组合，或SUR2B，VU0542270结合位点定位于SUR2.围绕VU0542270的初始结构-活性关系探索揭示了与Kir6.1/SUR2B抑制所需的结构元素相关的基本质地。对VU0542270的药代动力学特性的分析表明，由于广泛的代谢，其体内半衰期短。在离体小鼠动脉导管（DA）血管的压力肌电图实验中，VU0542270以类似于非特异性KATP通道抑制剂的剂量依赖性方式诱导DA收缩，格列本脲.VU0542270的发现提供了概念证明，可以使用基于分子靶标的方法开发SUR2特异性KATP通道抑制剂，并为开发靶向Kir6.1/SUR2B的心血管疗法提供了希望。意义陈述血管平滑肌KATP通道的小分子抑制剂可能代表动脉导管未闭的新疗法，偏头痛,和败血症,然而,缺乏选择性通道抑制剂减缓了这些治疗领域的进展.这里,我们描述了第一个血管特异性KATP通道抑制剂的发现和表征，VU0542270.
