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, 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.
Tsai
Ting-Yueh
TY
Division of Biotechnology and Pharmaceutical Research, National Health Research Institutes, No. 35, Keyan Road, Zhunan Town, Miaoli Country 350, Taiwan, R.O.C.
Yeh
Teng-Kuang
TK
Chen
Xin
X
Hsu
Tsu
T
Jao
Yu-Chen
YC
Huang
Chih-Hsiang
CH
Song
Jen-Shin
JS
Huang
Yu-Chen
YC
Chien
Chia-Hui
CH
Chiu
Jing-Huai
JH
Yen
Shih-Chieh
SC
Tang
Hung-Kuan
HK
Chao
Yu-Sheng
YS
Jiaang
Weir-Torn
WT
D000577:Amides / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D000818:Animals; D004150:Dipeptidases / Q000037:antagonists & inhibitors; D054873:Dipeptidyl-Peptidase IV Inhibitors; D004152:Dipeptidyl-Peptidases and Tripeptidyl-Peptidases / Q000037:antagonists & inhibitors; D010450:Endopeptidases; D018093:Gelatinases / Q000037:antagonists & inhibitors*; D006801:Humans; D008565:Membrane Proteins / Q000037:antagonists & inhibitors*; D051379:Mice; D008807:Mice, Inbred BALB C; D011761:Pyrrolidonecarboxylic Acid / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D012697:Serine Endopeptidases; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D000099167:Fibroblast Activation Protein Alpha
D000577:Amides; D004150:Dipeptidases; D054873:Dipeptidyl-Peptidase IV Inhibitors; D004152:Dipeptidyl-Peptidases and Tripeptidyl-Peptidases; D010450:Endopeptidases; D018093:Gelatinases; D008565:Membrane Proteins; D011761:Pyrrolidonecarboxylic Acid; D012697:Serine Endopeptidases; D000099167:Fibroblast Activation Protein Alpha; C471241:DPP9 protein, human; C100151:dipeptidyl peptidase II; C487997:DPP8 protein, human