Surrogating and redirection of pyrazolo[1,5-a]pyrimidin-7(4H)-one core, a novel class of potent and selective DPP-4 inhibitors

Bioorg Med Chem. 2018 Feb 15;26(4):903-912. doi: 10.1016/j.bmc.2018.01.006. Epub 2018 Jan 10.

Abstract

The initial focus on characterizing novel pyrazolo[1,5-a]pyrimidin-7(4H)-one derivatives as DPP-4 inhibitors, led to a potent and selective inhibitor compound b2. This ligand exhibits potent in vitro DPP-4 inhibitory activity (IC50: 80 nM), while maintaining other key cellular parameters such as high selectivity, low cytotoxicity and good cell viability. Subsequent optimization of b2 based on docking analysis and structure-based drug design knowledge resulted in d1. Compound d1 has nearly 2-fold increase of inhibitory activity (IC50: 49 nM) and over 1000-fold selectivity against DPP-8 and DPP-9. Further in vivo IPGTT assays showed that compound b2 effectively reduce glucose excursion by 34% at the dose of 10 mg/kg in diabetic mice. Herein we report the optimization and design of a potent and highly selective series of pyrazolo[1,5-a]pyrimidin-7(4H)-one DPP-4 inhibitors.

Keywords: Anti-diabetic; DPP-4 inhibitor; Molecular docking; Pyrazolo[1,5-a]pyrimidin-7(4H)-one derivatives; Structure-based drug design.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Binding Sites
  • Catalytic Domain
  • Cell Survival / drug effects
  • Diabetes Mellitus, Experimental / chemically induced
  • Diabetes Mellitus, Experimental / drug therapy
  • Diabetes Mellitus, Experimental / pathology
  • Dipeptidyl Peptidase 4 / chemistry
  • Dipeptidyl Peptidase 4 / metabolism*
  • Dipeptidyl-Peptidase IV Inhibitors / chemistry*
  • Dipeptidyl-Peptidase IV Inhibitors / pharmacology
  • Dipeptidyl-Peptidase IV Inhibitors / therapeutic use
  • Drug Design
  • Glucose Tolerance Test
  • Hep G2 Cells
  • Humans
  • Hypoglycemic Agents / chemistry*
  • Hypoglycemic Agents / pharmacology
  • Hypoglycemic Agents / therapeutic use
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Molecular Docking Simulation
  • Pyrazoles / chemistry*
  • Pyrazoles / pharmacology
  • Pyrazoles / therapeutic use
  • Pyrimidinones / chemistry*
  • Pyrimidinones / pharmacology
  • Pyrimidinones / therapeutic use
  • Structure-Activity Relationship

Substances

  • Dipeptidyl-Peptidase IV Inhibitors
  • Hypoglycemic Agents
  • Pyrazoles
  • Pyrimidinones
  • pyrazolo(1,5-a)pyrimidin-7(4H)-one
  • Dipeptidyl Peptidase 4