(R)-3-amino-1-((3aS,7aS)-octahydro-1H-indol-1-yl)-4-(2,4,5-trifluorophenyl)butan-1-one derivatives as potent inhibitors of dipeptidyl peptidase-4: design, synthesis, biological evaluation, and molecular modeling

Bioorg Med Chem. 2014 Dec 1;22(23):6684-6693. doi: 10.1016/j.bmc.2014.09.051. Epub 2014 Oct 23.

Abstract

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 IC50s of 0.07, 0.07, 0.14, and 0.17μM, 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%, t1/2=10.5h).

Keywords: Binding mode; DPP-4; Inhibitor; Oral bioavailability; Type 2 diabetes.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Dipeptidyl Peptidase 4 / metabolism*
  • Dose-Response Relationship, Drug
  • Drug Design*
  • Enzyme Inhibitors / chemical synthesis*
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacology*
  • Humans
  • Indoles / chemical synthesis
  • Indoles / chemistry
  • Indoles / pharmacology*
  • Models, Molecular*
  • Molecular Structure
  • Recombinant Proteins / metabolism
  • Structure-Activity Relationship
  • Sulfonamides / chemical synthesis
  • Sulfonamides / chemistry
  • Sulfonamides / pharmacology*

Substances

  • Enzyme Inhibitors
  • Indoles
  • N-((1-(3-amino-4-(2,4,5-trifluorophenyl)butanoyl)octahydro-1H-indol-2-yl)methyl)-1,1,1-trifluoromethanesulfonamide
  • Recombinant Proteins
  • Sulfonamides
  • DPP4 protein, human
  • Dipeptidyl Peptidase 4