title: Glutamic acid analogues as potent dipeptidyl peptidase IV and 8 inhibitors.
abstract: 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.
authors.affiliation: Division of Biotechnology and Pharmaceutical Research, National Health Research Institutes, No. 35, Keyan Rd., Zhunan Town, Miaoli Country 350, Taiwan, ROC.
authors.forename: I-Lin
authors.initials: IL
authors.lastname: Lu
authors.forename: Shiow-Ju
authors.initials: SJ
authors.lastname: Lee
authors.forename: Hsu
authors.initials: H
authors.lastname: Tsu
authors.forename: Su-Ying
authors.initials: SY
authors.lastname: Wu
authors.forename: Kuo-His
authors.initials: KH
authors.lastname: Kao
authors.forename: Chia-Hui
authors.initials: CH
authors.lastname: Chien
authors.forename: Ying-Ying
authors.initials: YY
authors.lastname: Chang
authors.forename: Yuan-Shou
authors.initials: YS
authors.lastname: Chen
authors.forename: Jai-Hong
authors.initials: JH
authors.lastname: Cheng
authors.forename: Chung-Nien
authors.initials: CN
authors.lastname: Chang
authors.forename: Tung-Wei
authors.initials: TW
authors.lastname: Chen
authors.forename: Sheng-Ping
authors.initials: SP
authors.lastname: Chang
authors.forename: Xin
authors.initials: X
authors.lastname: Chen
authors.forename: Weir-Torn
authors.initials: WT
authors.lastname: Jiaang
mesh_terms: 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
chemical_list: 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