(R)-3-Amino-1-((3as,7as)-Octahydro-1h-Indol-1-Yl)-4-(2,4,5-Trifluorophen Yl)Butan-1-One Derivatives As Potent Inhibitors Of Dipeptidyl Peptidase-4: Design, Synthesis, Biological Evaluation, And Molecular Modeling

A series of (R)-3-amino-1-((3aS,7aS)-octahydro-1H-indol-1-yl)-4-(2,4,5-trifluorophenyl)butan-1-one derivatives was designed, synthesized, and evaluated as novel inhibitors of dipeptidyl peptidase-4 (DPP-4) for the treatment of type 2 diabetes. Most of the synthesized compounds demonstrated good inhibition activities against DPP-4. Among these, compounds 3e, 4c, 4l, and 4n exhibited prominent inhibition activities against DPP-4, with IC(50)s of 0.07, 0.07, 0.14, and 0.17 mu M, respectively. The possible binding modes of compounds 3e and 4n with dipeptidyl peptidase-4 were also explored by molecular docking simulation. These potent DPP-4 inhibitors were optimized for the absorption, distribution, metabolism, and excretion (ADME) properties, and compound 4n displayed an attractive pharmacokinetic profile (F = 96.3%, t(1/2) = 10.5 h). (C) 2014 Elsevier Ltd. All rights reserved.