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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 IC(50) of <100 nM with excellent selectivity over DPP-IV, DPP-II, DPP8, and DPP9 (IC(50) > 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.

Citation

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 Jiaang. Substituted 4-carboxymethylpyroglutamic acid diamides as potent and selective inhibitors of fibroblast activation protein. Journal of medicinal chemistry. 2010 Sep 23;53(18):6572-83

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PMID: 20718420

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