(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.
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.
Yeh
Teng-Kuang
TK
Division of Biotechnology and Pharmaceutical Research, National Health Research Institutes, Zhunan Town, Miaoli Country, Taiwan, ROC.
Tsai
Ting-Yueh
TY
Hsu
Tsu
T
Cheng
Jai-Hong
JH
Chen
Xin
X
Song
Jen-Shin
JS
Shy
Horng-Shing
HS
Chiou
Mei-Chun
MC
Chien
Chia-Hui
CH
Tseng
Ya-Ju
YJ
Huang
Chung-Yu
CY
Yeh
Kai-Chia
KC
Huang
Yu-Lin
YL
Huang
Chih-Hsiang
CH
Huang
Yu-Wen
YW
Wang
Min-Hsien
MH
Tang
Hung-Kuan
HK
Chao
Yu-Sheng
YS
Chen
Chiung-Tong
CT
Jiaang
Weir-Torn
WT
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
D000588:Amines; D054873:Dipeptidyl-Peptidase IV Inhibitors; D009570:Nitriles; D011759:Pyrrolidines