Design, synthesis, and pharmacological evaluation of highly potent and selective dipeptidyl peptidase-4 inhibitors

Arch Pharm (Weinheim). 2015 Jun;348(6):399-407. doi: 10.1002/ardp.201500082. Epub 2015 Apr 14.

Abstract

The optimization of a series of fused β-homophenylalanine inhibitors of dipeptidyl peptidase-4 (DPP-4) is described. Modification on the P2-binding moiety of 6 (IC50 = 10 nM) led to the discovery of β-homophenylalanine derivatives containing pyrrolidin-2-ylmethyl amides. The introduction of a sulfamine in the meta position of the phenyl ring improved the potency against DPP-4 (6-12-fold increase). Compound 14k showed DPP-4 inhibitory activity with an IC50 value of 0.87 nM. Meanwhile, in vivo experiments exhibited that 14h had an efficiency comparable to sitagliptin at the dose of 10 mg/kg.

Keywords: DPP-4; Drug design; Inhibitors; P2-binding moiety; β-Homophenylalanine.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aminobutyrates / chemical synthesis*
  • Aminobutyrates / metabolism
  • Aminobutyrates / pharmacology*
  • Animals
  • Binding Sites
  • Biomarkers / blood
  • Blood Glucose / drug effects*
  • Blood Glucose / metabolism
  • Caco-2 Cells
  • Dipeptidyl Peptidase 4 / chemistry
  • Dipeptidyl Peptidase 4 / metabolism*
  • Dipeptidyl-Peptidase IV Inhibitors / chemical synthesis*
  • Dipeptidyl-Peptidase IV Inhibitors / metabolism
  • Dipeptidyl-Peptidase IV Inhibitors / pharmacology*
  • Drug Design*
  • Humans
  • Male
  • Mice, Inbred C57BL
  • Molecular Docking Simulation
  • Protein Binding
  • Protein Conformation
  • Sitagliptin Phosphate / pharmacology
  • Structure-Activity Relationship
  • Time Factors

Substances

  • Aminobutyrates
  • Biomarkers
  • Blood Glucose
  • Dipeptidyl-Peptidase IV Inhibitors
  • 2-amino-4-phenylbutyric acid
  • DPP4 protein, human
  • Dipeptidyl Peptidase 4
  • Dpp4 protein, mouse
  • Sitagliptin Phosphate