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[摘要]：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. |
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