Glutamic acid analogues as potent dipeptidyl peptidase IV and 8 inhibitors.
To find potent and selective inhibitors of dipeptidyl peptidase IV (DPP-IV), we synthesized a series of 2-cyanopyrrolidine with P2-site 4-substituted glutamic acid derivatives and tested their activities against DPP-IV, DPP8, and DPP-II. Analogues that incorporated a bulky substituent at the first carbon position of benzylamine or isoquinoline showed over 30-fold selectivity for DPP-IV over both DPP8 and DPP-II. From structure-activity relationship studies, we speculate that the S2 site of DPP8 might be similar to that of DPP-IV, while DPP-IV inhibitor with N-substituted glycine in the P2 site and/or with a moiety involving in hydrophobic interaction with the side chain of Phe357 might provide a better selectivity for DPP-IV over DPP8.
Lu
I-Lin
IL
Division of Biotechnology and Pharmaceutical Research, National Health Research Institutes, No. 35, Keyan Rd., Zhunan Town, Miaoli Country 350, Taiwan, ROC.
Lee
Shiow-Ju
SJ
Tsu
Hsu
H
Wu
Su-Ying
SY
Kao
Kuo-His
KH
Chien
Chia-Hui
CH
Chang
Ying-Ying
YY
Chen
Yuan-Shou
YS
Cheng
Jai-Hong
JH
Chang
Chung-Nien
CN
Chen
Tung-Wei
TW
Chang
Sheng-Ping
SP
Chen
Xin
X
Jiaang
Weir-Torn
WT
D058892:Adenosine Deaminase Inhibitors; D001665:Binding Sites; D004150:Dipeptidases / Q000037:antagonists & inhibitors; D018819:Dipeptidyl Peptidase 4; D004152:Dipeptidyl-Peptidases and Tripeptidyl-Peptidases / Q000037:antagonists & inhibitors*; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D018698:Glutamic Acid / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology; D006023:Glycoproteins / Q000037:antagonists & inhibitors; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D020128:Inhibitory Concentration 50; D008958:Models, Molecular; D011485:Protein Binding; D011759:Pyrrolidines / Q000138:chemical synthesis / Q000494:pharmacology; D013329:Structure-Activity Relationship
D058892:Adenosine Deaminase Inhibitors; D004791:Enzyme Inhibitors; D006023:Glycoproteins; D011759:Pyrrolidines; D018698:Glutamic Acid; D004150:Dipeptidases; D004152:Dipeptidyl-Peptidases and Tripeptidyl-Peptidases; C100151:dipeptidyl peptidase II; C042807:DPP4 protein, human; C487997:DPP8 protein, human; D018819:Dipeptidyl Peptidase 4