Lippa Blaise, Morris Joel, Corbett Matthew, Kwan Tricia A, Noe Mark C, Snow Sheri L, Gant Thomas G, Mangiaracina Melchiorra, Coffey Heather A, Foster Barbara, Knauth Elisabeth A, Wessel Matthew D
Pfizer Inc., PGRD Groton, MS-8220-2203 Eastern Point Rd., Groton, CT 06340, USA.
Bioorg Med Chem Lett. 2006 Jul 1;16(13):3444-8. doi: 10.1016/j.bmcl.2006.04.003. Epub 2006 Apr 24.
The design, synthesis, and biological evaluation of potent inhibitors of the TrkA kinase is presented. A homology model is created to aid in the enhancement of potency and selectivity of isothiazole inhibitors found during a high-throughput screen. Three different syntheses are utilized to make diverse analogs within this series. Aminoheterocycles are found to be good urea surrogates, whereas bicyclic substituents on the C3 thio group were found to be extremely potent TrkA inhibitors in kinase and cell assays.
本文介绍了TrkA激酶强效抑制剂的设计、合成及生物学评价。构建了一个同源模型，以帮助提高在高通量筛选中发现的异噻唑抑制剂的效力和选择性。利用三种不同的合成方法来制备该系列中的多种类似物。发现氨基杂环是良好的脲替代物，而C3硫基上的双环取代基在激酶和细胞试验中被发现是极其有效的TrkA抑制剂。
