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

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,...

Full description

Saved in:
Bibliographic Details
Published in:Journal of medicinal chemistry 2010-09, Vol.53 (18), p.6572-6583
Main Authors: Tsai, Ting-Yueh, Yeh, Teng-Kuang, Chen, Xin, Hsu, Tsu, Jao, Yu-Chen, Huang, Chih-Hsiang, Song, Jen-Shin, Huang, Yu-Chen, Chien, Chia-Hui, Chiu, Jing-Huai, Yen, Shih-Chieh, Tang, Hung-Kuan, Chao, Yu-Sheng, Jiaang, Weir-Torn
Format: Article
Language:English
Subjects:
Amides - chemical synthesis
Amides - pharmacokinetics
Amides - pharmacology
Animals
Dipeptidases - antagonists & inhibitors
Dipeptidyl-Peptidase IV Inhibitors
Dipeptidyl-Peptidases and Tripeptidyl-Peptidases - antagonists & inhibitors
Gelatinases - antagonists & inhibitors
Humans
Membrane Proteins - antagonists & inhibitors
Mice
Mice, Inbred BALB C
Pyrrolidonecarboxylic Acid - analogs & derivatives
Pyrrolidonecarboxylic Acid - chemical synthesis
Pyrrolidonecarboxylic Acid - pharmacokinetics
Pyrrolidonecarboxylic Acid - pharmacology
Serine Endopeptidases
Stereoisomerism
Structure-Activity Relationship
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary: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 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.
ISSN:0022-2623
1520-4804
DOI:10.1021/jm1002556