Substituted 4-Carboxymethylpyroglutamic Acid Diamides as Potent and Selective Inhibitors of Fibroblast Activation Protein

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• 作者：Ting-Yueh Tsai ; Teng-Kuang Yeh ; Xin Chen ; Tsu Hsu ; Yu-Chen Jao ; Chih-Hsiang Huang ; Jen-Shin Song ; Yu-Chen Huang ; Chia-Hui Chien ; Jing-Huai Chiu ; Shih-Chieh Yen ; Hung-Kuan Tang ; Yu-Sheng Chao ; Weir-Torn
• 刊名：Journal of Medicinal Chemistry
• 出版年：2010
• 出版时间：September 23, 2010
• 年：2010
• 卷：53
• 期：18
• 页码：6572-6583
• 全文大小：1033K
• 年卷期：v.53,no.18(September 23, 2010)
• ISSN：1520-4804

文摘

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 P1 site; however, these inhibitors also inhibit DPP-IV, DPP-II, DPP8, and DPP9. Potent and selective FAP inhibitor is needed in evaluating that FAP 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. SAR 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 μM). Compounds 18a, 18b, and 19 are the only known potent and selective FAP inhibitors, which prompts us to further study the physiological role of FAP.