3-[2-((2S)-2-cyano-pyrrolidin-1-yl)-2-oxo-ethylamino]-3-methyl-butyramide analogues as selective DPP-IV inhibitors for the treatment of type-II diabetes.
Based on the structures of NVP-DPP728 (1) and NVP-LAF237 (Vildagliptin, 2), three series of DPP-IV inhibitors were synthesized by linking substituted anilines, benzylamines, and phenylethylamines to (2S)-cyanopyrrolidine through a linker. More than 20 compounds were evaluated for their in vitro DPP-IV inhibition and selectivity profile over DPP-II, DPP8, and FAP enzymes. Selected compounds 5f and 7i showed in vivo plasma DPP-IV inhibition and inhibited glucose excursion in OGTT after oral administration in Wistar rats. Compound 5f (DPP-IV IC50 = 116 nM) has the potential for development as antidiabetic agent.
Coumar
Mohane Selvaraj
MS
Division of Biotechnology and Pharmaceutical Research, National Health Research Institutes, No. 35, Keyan Rd., Zhunan Town, Miaoli County 350, Taiwan, ROC.
Chang
Chung-Nien
CN
Chen
Chiung-Tong
CT
Chen
Xin
X
Chien
Chia-Hui
CH
Tsai
Ting-Yueh
TY
Cheng
Jai-Hong
JH
Wu
Hsin-Yi
HY
Han
Chia-Hung
CH
Wu
Ssu-Hui
SH
Huang
Yu-Wen
YW
Hsu
Tsu
T
Hsu
Li-Jen
LJ
Chao
Yu-Sheng
YS
Hsieh
Hsing-Pang
HP
Jiaang
Weir-Torn
WT
D000218:Adamantane / Q000031:analogs & derivatives; D058892:Adenosine Deaminase Inhibitors; D000577:Amides / Q000138:chemical synthesis / Q000494:pharmacology*; D000814:Aniline Compounds; D000818:Animals; D001596:Benzylamines; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy*; D018819:Dipeptidyl Peptidase 4; D054873:Dipeptidyl-Peptidase IV Inhibitors; D006023:Glycoproteins / Q000037:antagonists & inhibitors*; D020128:Inhibitory Concentration 50; D009570:Nitriles; D010627:Phenethylamines; D011759:Pyrrolidines; D051381:Rats; D017208:Rats, Wistar; D013329:Structure-Activity Relationship; D000077597:Vildagliptin
C121834:1-(((2-((5-cyanopyridin-2-yl)amino)ethyl)amino)acetyl)-2-cyano-(S)-pyrrolidine; D058892:Adenosine Deaminase Inhibitors; D000577:Amides; D000814:Aniline Compounds; D001596:Benzylamines; D054873:Dipeptidyl-Peptidase IV Inhibitors; D006023:Glycoproteins; D009570:Nitriles; D010627:Phenethylamines; D011759:Pyrrolidines; C006866:butyramide; C042807:DPP4 protein, human; D018819:Dipeptidyl Peptidase 4; D000077597:Vildagliptin; D000218:Adamantane