title: Rational design and synthesis of potent and long-lasting glutamic acid-based dipeptidyl peptidase IV inhibitors.
abstract: A series of (2S)-cyanopyrrolidines with glutamic acid derivatives at the P2 site have been prepared and evaluated as inhibitors of dipeptidyl peptidase IV (DPP-IV). The structure-activity relationships (SAR) led to the discovery of potent 3-substituted glutamic acid analogues, providing enhanced chemical stability and excellent selectivity over the closely related enzymes, DPP8, DPP-II and FAP. Compound 13f exhibited the ability to both significantly decrease the glucose excursion and inhibit plasma DPP-IV activity.
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: Ting-Yueh
authors.initials: TY
authors.lastname: Tsai
authors.forename: Tsu
authors.initials: T
authors.lastname: Hsu
authors.forename: Chiung-Tong
authors.initials: CT
authors.lastname: Chen
authors.forename: Jai-Hong
authors.initials: JH
authors.lastname: Cheng
authors.forename: Mei-Chun
authors.initials: MC
authors.lastname: Chiou
authors.forename: Chih-Hsiang
authors.initials: CH
authors.lastname: Huang
authors.forename: Ya-Ju
authors.initials: YJ
authors.lastname: Tseng
authors.forename: Teng-Kuang
authors.initials: TK
authors.lastname: Yeh
authors.forename: Chung-Yu
authors.initials: CY
authors.lastname: Huang
authors.forename: Kai-Chia
authors.initials: KC
authors.lastname: Yeh
authors.forename: Yu-Wen
authors.initials: YW
authors.lastname: Huang
authors.forename: Ssu-Hui
authors.initials: SH
authors.lastname: Wu
authors.forename: Min-Hsien
authors.initials: MH
authors.lastname: Wang
authors.forename: Xin
authors.initials: X
authors.lastname: Chen
authors.forename: Yu-Sheng
authors.initials: YS
authors.lastname: Chao
authors.forename: Weir-Torn
authors.initials: WT
authors.lastname: Jiaang
mesh_terms: D000284:Administration, Oral; D000818:Animals; D018819:Dipeptidyl Peptidase 4 / Q000097:blood / Q000378:metabolism; D054873:Dipeptidyl-Peptidase IV Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D015195:Drug Design; D005947:Glucose / Q000378:metabolism; D018698:Glutamic Acid / Q000737:chemistry*; D051379:Mice; D008810:Mice, Inbred C57BL; D011759:Pyrrolidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship
chemical_list: D054873:Dipeptidyl-Peptidase IV Inhibitors; D011759:Pyrrolidines; D018698:Glutamic Acid; D018819:Dipeptidyl Peptidase 4; D005947:Glucose