Medicinal Chemistry, CNSP iMed Science, AstraZeneca R&D, Innovative Medicines, SE-15185 Södertälje, Sweden.
Bioorg Med Chem Lett. 2012 Oct 1;22(19):6108-15. doi: 10.1016/j.bmcl.2012.08.031. Epub 2012 Aug 14.
The Na(V)1.7 ion channel is an attractive target for development of potential analgesic drugs based on strong genetic links between mutations in the gene coding for the channel protein and inheritable pain conditions. The (S)-N-chroman-3-ylcarboxamide series, exemplified by 1, was used as a starting point for development of new channel blockers, resulting in the phenethyl nicotinamide series. The structure and activity relationship for this series was established and the metabolic issues of early analogues were addressed by appropriate substitutions. Compound 33 displayed acceptable overall in vitro properties and in vivo rat PK profile.
钠离子通道 Na(V)1.7 是开发潜在止痛药物的一个有吸引力的靶点，这是基于通道蛋白编码基因中的突变与遗传性疼痛病症之间存在很强的遗传联系。（S）-N-色满-3-甲酰胺系列，以化合物 1 为代表，被用作开发新的通道阻滞剂的起点，从而产生了苯乙基烟酰胺系列。该系列的结构与活性关系已经建立，早期类似物的代谢问题通过适当的取代得到解决。化合物 33 表现出可接受的整体体外特性和体内大鼠 PK 特征。
