title: (2S,4S)-1-[2-(1,1-dimethyl-3-oxo-3-pyrrolidin-1-yl-propylamino)acetyl]-4-fluoro-pyrrolidine-2-carbonitrile: a potent, selective, and orally bioavailable dipeptide-derived inhibitor of dipeptidyl peptidase IV.
abstract: A series of 2-[3-[2-[(2S)-2-cyano-1-pyrrolidinyl]-2-oxoethylamino]-3-methyl-1-oxobutyl]-based DPP-IV inhibitors with various monocyclic amines were synthesized. The structure-activity relationships (SAR) led to the discovery of potent DPP-IV inhibitors, having IC(50) values of <100 nM with excellent selectivity over the closely related enzymes, DPP-II, DPP8, DPP9 and FAP (IC(50)>20 microM). Of these compounds, the analogues 12a, 12h and 12i exhibited a long-lasting ex vivo DPP-IV inhibition in rats.
authors.affiliation: Division of Biotechnology and Pharmaceutical Research, National Health Research Institutes, Zhunan Town, Miaoli Country, Taiwan, ROC.
authors.forename: Teng-Kuang
authors.initials: TK
authors.lastname: Yeh
authors.forename: Ting-Yueh
authors.initials: TY
authors.lastname: Tsai
authors.forename: Tsu
authors.initials: T
authors.lastname: Hsu
authors.forename: Jai-Hong
authors.initials: JH
authors.lastname: Cheng
authors.forename: Xin
authors.initials: X
authors.lastname: Chen
authors.forename: Jen-Shin
authors.initials: JS
authors.lastname: Song
authors.forename: Horng-Shing
authors.initials: HS
authors.lastname: Shy
authors.forename: Mei-Chun
authors.initials: MC
authors.lastname: Chiou
authors.forename: Chia-Hui
authors.initials: CH
authors.lastname: Chien
authors.forename: Ya-Ju
authors.initials: YJ
authors.lastname: Tseng
authors.forename: Chung-Yu
authors.initials: CY
authors.lastname: Huang
authors.forename: Kai-Chia
authors.initials: KC
authors.lastname: Yeh
authors.forename: Yu-Lin
authors.initials: YL
authors.lastname: Huang
authors.forename: Chih-Hsiang
authors.initials: CH
authors.lastname: Huang
authors.forename: Yu-Wen
authors.initials: YW
authors.lastname: Huang
authors.forename: Min-Hsien
authors.initials: MH
authors.lastname: Wang
authors.forename: Hung-Kuan
authors.initials: HK
authors.lastname: Tang
authors.forename: Yu-Sheng
authors.initials: YS
authors.lastname: Chao
authors.forename: Chiung-Tong
authors.initials: CT
authors.lastname: Chen
authors.forename: Weir-Torn
authors.initials: WT
authors.lastname: Jiaang
mesh_terms: D000284:Administration, Oral; D000588:Amines; D000818:Animals; D001682:Biological Availability; D054873:Dipeptidyl-Peptidase IV Inhibitors / Q000008:administration & dosage / Q000138:chemical synthesis* / Q000493:pharmacokinetics; D020128:Inhibitory Concentration 50; D009570:Nitriles / Q000138:chemical synthesis* / Q000494:pharmacology; D011759:Pyrrolidines / Q000138:chemical synthesis* / Q000494:pharmacology; D051381:Rats; D013329:Structure-Activity Relationship
chemical_list: D000588:Amines; D054873:Dipeptidyl-Peptidase IV Inhibitors; D009570:Nitriles; D011759:Pyrrolidines