Medicinal Chemistry, CNSP iMed Science, AstraZeneca R&D, Innovative Medicines, SE-15185 Södertälje, Sweden.
Bioorg Med Chem Lett. 2011 Jul 1;21(13):3871-6. doi: 10.1016/j.bmcl.2011.05.041. Epub 2011 May 18.
Blocking of certain sodium channels is considered to be an attractive mechanism to treat chronic pain conditions. Phenyl isoxazole carbamate 1 was identified as a potent and selective Na(V)1.7 blocker. Structural analogues of 1, both carbamates, ureas and amides, were proven to be useful in establishing the structure-activity relationship and improving ADME related properties. Amide 24 showed a good overall in vitro profile, that translated well to rat in vivo PK.
阻断某些钠通道被认为是治疗慢性疼痛疾病的一种有吸引力的机制。苯并异恶唑基氨基甲酸酯 1 被鉴定为一种有效的、选择性的 Na(V)1.7 阻断剂。1 的结构类似物，包括氨基甲酸酯、脲和酰胺，被证明在建立构效关系和改善 ADME 相关性质方面很有用。酰胺 24 表现出良好的整体体外特性，在大鼠体内 PK 中也得到了很好的体现。
