3-[2-((2 S)-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 (2 S)-cyanopyrrolidine through a linker. More than 20 compounds were evaluated for their in vitro DP...

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Published in:Bioorganic & medicinal chemistry letters 2007-03, Vol.17 (5), p.1274-1279
Main Authors: Coumar, Mohane Selvaraj, Chang, Chung-Nien, Chen, Chiung-Tong, Chen, Xin, Chien, Chia-Hui, Tsai, Ting-Yueh, Cheng, Jai-Hong, Wu, Hsin-Yi, Han, Chia-Hung, Wu, Ssu-Hui, Huang, Yu-Wen, Hsu, Tsu, Hsu, Li-Jen, Chao, Yu-Sheng, Hsieh, Hsing-Pang, Jiaang, Weir-Torn
Format: Article
Language:English
Subjects:
Adamantane - analogs & derivatives
Adenosine Deaminase Inhibitors
Amides - chemical synthesis
Amides - pharmacology
Aniline Compounds
Animals
Benzylamines
Biological and medical sciences
Diabetes Mellitus, Type 2 - drug therapy
Dipeptidyl Peptidase 4
Dipeptidyl-Peptidase IV Inhibitors
DPP-IV
General and cellular metabolism. Vitamins
Glycoproteins - antagonists & inhibitors
Inhibitory Concentration 50
Medical sciences
Nitriles
Pharmacology. Drug treatments
Phenethylamines
Pyrrolidines
Rats
Rats, Wistar
Structure-Activity Relationship
Type-II diabetes
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Summary: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 (2 S)-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 IC 50 = 116 nM) has the potential for development as antidiabetic agent.
ISSN:0960-894X
1464-3405
DOI:10.1016/j.bmcl.2006.12.019