Rational design and synthesis of potent and long-lasting glutamic acid-based dipeptidyl peptidase IV inhibitors.
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.
Tsai
Ting-Yueh
TY
Division of Biotechnology and Pharmaceutical Research, National Health Research Institutes, No. 35, Keyan Rd., Zhunan Town, Miaoli Country 350, Taiwan, ROC.
Hsu
Tsu
T
Chen
Chiung-Tong
CT
Cheng
Jai-Hong
JH
Chiou
Mei-Chun
MC
Huang
Chih-Hsiang
CH
Tseng
Ya-Ju
YJ
Yeh
Teng-Kuang
TK
Huang
Chung-Yu
CY
Yeh
Kai-Chia
KC
Huang
Yu-Wen
YW
Wu
Ssu-Hui
SH
Wang
Min-Hsien
MH
Chen
Xin
X
Chao
Yu-Sheng
YS
Jiaang
Weir-Torn
WT
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
D054873:Dipeptidyl-Peptidase IV Inhibitors; D011759:Pyrrolidines; D018698:Glutamic Acid; D018819:Dipeptidyl Peptidase 4; D005947:Glucose