Substituted 4-Carboxymethylpyroglutamic Acid Diamides as Potent and Selective Inhibitors of Fibroblast Activation Protein
Substituted 4-Carboxymethylpyroglutamic Acid Diamides as Potent and Selective Inhibitors of Fibroblast Activation Protein
复制标题
DOI：
10.1021/jm1002556
复制
发表时间：
2010-09-23
影响因子：
7.3
通讯作者：
Jiaang, Weir-Torn
中科院分区：
文献类型：
--
作者：
Tsai, Ting-Yueh;Yeh, Teng-Kuang;Jiaang, Weir-Torn
成纤维细胞活化蛋白（FAP）属于脯氨酸肽酶家族。抑制FAP有望成为新的抗肿瘤靶点。大多数已知的FAP抑制剂通常类似于二肽裂解产物，在PI位点有一个硼脯氨酸；然而，这些抑制剂也抑制DPP-IV， DPP-II， DPP8和DPP9。在评估FA - P作为治疗靶点时，需要有效和选择性的FAN抑制剂。因此，开发选择性FAP抑制剂用于靶标验证非常重要，为了实现这一目标，对非选择性DPP-IV抑制剂8进行了优化，发现了一类新的取代4-羧基甲基焦谷氨酸二胺作为FAP抑制剂。SA - R研究结果表明，许多FAP抑制剂的IC50 < 100 nM，对DPP-IV、DPP-II具有良好的选择性。DPP8和DPP9 （IC50 bb0 100亩）。化合物18a， 18b和19是已知的唯一有效的选择性FAP抑制剂，这促使我们进一步研究FAP的生理作用。
Fibroblast activation protein (FAP) belongs to the prolyl peptidase family. FAP inhibition is expected to become a new antitumor target. Most known FAP inhibitors often resemble the dipeptide cleavage products, with a boroproline at the PI site; however, these inhibitors also inhibit DPP-IV, DPP-II, DPP8, and DPP9. Potent and selective FAN inhibitor is needed in evaluating that FA P as a therapeutic target. Therefore, it is important to develop selective FAP inhibitors for the use of target validation, To achieve this, optimization of the nonselective DPP-IV inhibitor 8 led to the discovery of a new class of substituted 4-carboxymethylpyroglutamic acid diamides as FAP inhibitors. SA R studies resulted in a number of FAP inhibitors having IC50 of < 100 nM with excellent selectivity over DPP-IV, DPP-II. DPP8, and DPP9 (IC50 > 100 mu M). Compounds 18a, 18b, and 19 are the only known potent and selective FA P inhibitors, which prompts us to further study the physiological role of FAP.