Medicinal Chemistry, CNSP iMed Science, AstraZeneca R&D, Innovative Medicines, SE-15185 Södertälje, Sweden.
Bioorg Med Chem Lett. 2012 Sep 1;22(17):5618-24. doi: 10.1016/j.bmcl.2012.06.105. Epub 2012 Jul 7.
Recent findings showing a relation between mutations in the Na(V)1.7 channel in humans and altered pain sensation has contributed to increase the attractiveness of this ion channel as target for development of potential analgesics. Amido chromanes 1 and 2 were identified as blockers of the Na(V)1.7 channel and analogues with modifications of the 5-substituent and the carboxamide part of the molecule were prepared to establish the structure-activity relationship. Compounds 13 and 29 with good overall in vitro and in vivo rat PK profile were identified. Furthermore, 29 showed in vivo efficacy in a nociceptive pain model.
最近的研究发现，人类钠离子通道 1.7 型（Na(V)1.7）的突变与痛觉改变之间存在关联，这使得该离子通道成为开发潜在镇痛药物的目标的吸引力增加。酰胺色满 1 和 2 被鉴定为钠离子通道 1.7 型的阻断剂，并且对分子的 5 位取代基和羧酰胺部分进行修饰得到了类似物，以建立构效关系。鉴定了具有良好的整体体外和体内大鼠药代动力学特征的化合物 13 和 29。此外，29 在伤害性疼痛模型中表现出体内疗效。
