Synthetic small molecule GLP-1 secretagogues prepared by means of a three-component indole annulation strategy.
Synthetic small molecule GLP-1 secretagogues prepared by means of a three-component indole annulation strategy.
复制标题
合成小分子GLP-1通过三组分吲哚环状策略制备的促进glp-1。
DOI：
10.1038/srep28934
复制
发表时间：
2016-06-29
影响因子：
4.6
通讯作者：
Holz GG
中科院分区：
文献类型：
--
作者：
Chepurny OG;Leech CA;Tomanik M;DiPoto MC;Li H;Han X;Meng Q;Cooney RN;Wu J;Holz GG
用于药物发现目的的小分子文库的合理组装需要一种有效的方法，其中能够合成生物活性化合物，使得可以衍生出具有类似基本制剂的许多结构相关的化合物。在这里，我们描述了（4 + 3）和（3 + 2）吲哚成环策略，快速生成复杂的吲哚杂环库，包含新的环庚-和环戊[B]吲哚，分别。筛选包含这些吲哚的一个这样的文库鉴定JWU-A021是体外胰高血糖素样肽-1（GLP-1）分泌的特别有效的刺激剂。令人惊讶的是，JWU-A021也是通过TRPA 1阳离子通道的Ca 2+内流的有效刺激剂（EC 50 ca. 200 nM），从而解释了其刺激GLP-1释放的能力。另外重要的是，现有证据表明JWU-A021是文献中尚未报道的最有效的非亲电TRPA-1通道激动剂之一。
Rational assembly of small molecule libraries for purposes of drug discovery requires an efficient approach in which the synthesis of bioactive compounds is enabled so that numerous structurally related compounds of a similar basic formulation can be derived. Here, we describe (4 + 3) and (3 + 2) indole annulation strategies that quickly generate complex indole heterocycle libraries that contain novel cyclohepta- and cyclopenta[b]indoles, respectively. Screening of one such library comprised of these indoles identifies JWU-A021 to be an especially potent stimulator of glucagon-like peptide-1 (GLP-1) secretion in vitro. Surprisingly, JWU-A021 is also a potent stimulator of Ca2+ influx through TRPA1 cation channels (EC50 ca. 200 nM), thereby explaining its ability to stimulate GLP-1 release. Of additional importance, the available evidence indicates that JWU-A021 is one of the most potent non-electrophilic TRPA-1 channel agonists yet to be reported in the literature.