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

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 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.

journal_name

J Med Chem

journal_title

Journal of medicinal chemistry

authors

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

doi

10.1021/jm1002556

subject

Has Abstract

pub_date

2010-09-23 00:00:00

pages

6572-83

issue

18

eissn

0022-2623

issn

1520-4804

journal_volume

53

pub_type

杂志文章

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