Tripathy Rabindranath, Angeles Thelma S, Yang Shi X, Mallamo John P
Cephalon, Inc., Discovery Research, 145 Brandywine Parkway, West Chester, PA 19380, USA.
Bioorg Med Chem Lett. 2008 Jun 15;18(12):3551-5. doi: 10.1016/j.bmcl.2008.05.012. Epub 2008 May 6.
An immobilized Staurosporine aglycone isostere where one of the indole nitrogen atoms was replaced by carbon has been sequentially functionalized to generate compounds inhibiting TrkA kinase. In the first phase, initial screening of a library of C13-hydroxymethyl-7-oxo-indenopyrrolocarbazoles resulted in several potent compounds, one of which was further optimized to generate the corresponding carbamates on solid phase. Some of the major carbamate diastereomers were found to be several-fold more potent than their alcohol parents. Synthesis, SAR analysis, kinase selectivity, and anti-tumor properties of a TrkA inhibitor (12a) are discussed.
一种固定化的星形孢菌素苷元类似物（其中一个吲哚氮原子被碳取代）已被依次官能化以生成抑制TrkA激酶的化合物。在第一阶段，对C13-羟甲基-7-氧代-茚并吡咯并咔唑文库的初步筛选产生了几种强效化合物，其中一种进一步优化以在固相上生成相应的氨基甲酸酯。发现一些主要的氨基甲酸酯非对映异构体比其醇母体的效力高几倍。讨论了TrkA抑制剂（12a）的合成、构效关系分析、激酶选择性和抗肿瘤特性。
