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

Bioorg Med Chem Lett. 2007 Mar 1;17(5):1274-9. doi: 10.1016/j.bmcl.2006.12.019. Epub 2006 Dec 12.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adamantane / analogs & derivatives
  • Adenosine Deaminase Inhibitors*
  • Amides / chemical synthesis
  • Amides / pharmacology*
  • Aniline Compounds
  • Animals
  • Benzylamines
  • Diabetes Mellitus, Type 2 / drug therapy*
  • Dipeptidyl Peptidase 4
  • Dipeptidyl-Peptidase IV Inhibitors*
  • Glycoproteins / antagonists & inhibitors*
  • Inhibitory Concentration 50
  • Nitriles
  • Phenethylamines
  • Pyrrolidines
  • Rats
  • Rats, Wistar
  • Structure-Activity Relationship
  • Vildagliptin

Substances

  • 1-(((2-((5-cyanopyridin-2-yl)amino)ethyl)amino)acetyl)-2-cyano-(S)-pyrrolidine
  • Adenosine Deaminase Inhibitors
  • Amides
  • Aniline Compounds
  • Benzylamines
  • Dipeptidyl-Peptidase IV Inhibitors
  • Glycoproteins
  • Nitriles
  • Phenethylamines
  • Pyrrolidines
  • butyramide
  • DPP4 protein, human
  • Dipeptidyl Peptidase 4
  • Vildagliptin
  • Adamantane