Synthesis, biological assay in vitro and molecular docking studies of new imidazopyrazinone derivatives as potential dipeptidyl peptidase IV inhibitors

• DOI: 10.1016/j.ejmech.2010.08.002
• Publication Date: 2010-08-13T09:14:41Z
• Authors: Yanyun Zhu; Shuang Xia; Mingjie Zhu; Weiyin Yi; Jiagao Cheng; Gonghua Song; Zhong Li; Peng Lu
• Keywords: Dipeptidyl peptidase; Docking (animal); Moiety; Molecular model; IC50

A series of novel imidazopyrazinone derivatives were synthesized and evaluated with regard to their ability to inhibit dipeptidyl peptidase IV (DPP-IV) in vitro. Of these compounds (2R)-4-oxo-4-[2-(3-carbamoylbenzyl)-hexahydro-3-oxoimidazo [1,5-a]pyrazin-7(8H)-yl]-1-(2,4,5-trifluorophenyl)butan-2-amine fumaric acid (17h, IC(50)=78 nM) was shown to effectively inhibit the activity of the dipeptidyl peptidase IV enzyme. Molecular docking studies were also performed to illustrate the binding mode of compounds 15c and 17h. Favorable interactions were identified from the binding of inhibitor 15c with DPP-IV. By analogy to the binding mode of compound 15c, it seems that the introduction of a substituted benzyl moiety onto the imidazopyrazinone could remarkably improve the inhibitory activity of compound 17h.