Abbott Laboratories, Neuroscience Research, Global Pharmaceutical Research and Development, Abbott Park, IL 60064-6101, United States.
Bioorg Med Chem Lett. 2011 Jun 1;21(11):3297-300. doi: 10.1016/j.bmcl.2011.04.024. Epub 2011 Apr 14.
Synthesis and biological evaluation of a novel class of substituted N-benzyl-1-(2,3-dichlorophenyl)-1H-tetrazol-5-amine derivatives resulted in the identification of potent P2X(7) antagonists. These compounds were assayed for activity at both the human and rat P2X(7) receptors. On the benzyl moiety, a variety of functional groups were tolerated, including both electron-withdrawing and electron-donating substituents. Ortho-substitution on the benzyl group provided the greatest potency. The ortho-substituted analogs showed approximately 2.5-fold greater potency at human compared to rat P2X(7) receptors. Compounds 12 and 38 displayed hP2X(7)pIC(50)s>7.8 with less than 2-fold difference in potency at the rP2X(7).
新型取代的 N-苄基-1-(2,3-二氯苯基)-1H-四唑-5-胺衍生物的合成与生物评价导致了强效 P2X(7) 拮抗剂的发现。这些化合物在人和大鼠 P2X(7) 受体上进行了活性测定。在苄基部分，各种官能团都可以被容忍，包括吸电子和供电子取代基。苄基上的邻位取代提供了最大的活性。与大鼠 P2X(7) 受体相比，邻位取代的类似物在人 P2X(7) 受体上的活性约高 2.5 倍。化合物 12 和 38 对 hP2X(7)pIC(50) 的作用>7.8，在 rP2X(7)上的活性差异小于 2 倍。
