Substituted 4-carboxymethylpyroglutamic acid diamides as potent and selective inhibitors of fibroblast activation protein.

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Tsai TY, Yeh TK, Chen X, Hsu T, Jao YC, Huang CH, Song JS, Huang YC, Chien CH, Chiu JH, Yen SC, Tang HK, Chao YS, Jiaang WT

Substituted 4-carboxymethylpyroglutamic acid diamides as potent and selective inhibitors of fibroblast activation protein.

J Med Chem. 2010 Sep 23;53(18):6572-83. doi: 10.1021/jm1002556.

PubMed ID

20718420 [ View in PubMed

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Abstract

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 muM). 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.

DrugBank Data that Cites this Article

Binding Properties

Drug	Target	Property	Measurement	pH	Temperature (°C)
Sitagliptin	Dipeptidyl peptidase 4	IC 50 (nM)	23	N/A	N/A	Details
Vildagliptin	Dipeptidyl peptidase 4	IC 50 (nM)	56	N/A	N/A	Details