The highly potent and selective dipeptidyl peptidase IV inhibitors bearing a thienopyrimidine scaffold effectively treat type 2 diabetes

Eur J Med Chem. 2011 Jan;46(1):71-6. doi: 10.1016/j.ejmech.2010.10.016. Epub 2010 Oct 26.

Abstract

New dipeptidyl peptidase IV inhibitors were designed based on Alogliptin using a scaffold-hopping strategy. All of the compounds constructed on a thienopyrimidine scaffold demonstrated good inhibition and selectivity for DPP-IV. Compound 10d exhibited subnanomolar (IC(50)=0.33nM) DPP-IV inhibitory activity, good in vivo efficacy and an acceptable pharmacokinetic profile. A pharmacokinetic-driven optimization of 10d may lead to a new class of clinical candidate DPP-IV inhibitors.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Blood Glucose / metabolism
  • Diabetes Mellitus, Type 2 / drug therapy*
  • Dipeptidyl Peptidase 4 / metabolism*
  • Dipeptidyl-Peptidase IV Inhibitors / chemistry*
  • Dipeptidyl-Peptidase IV Inhibitors / pharmacokinetics
  • Dipeptidyl-Peptidase IV Inhibitors / pharmacology*
  • Dipeptidyl-Peptidase IV Inhibitors / therapeutic use
  • Dogs
  • Drug Discovery
  • HEK293 Cells
  • Humans
  • Male
  • Piperidines / chemistry
  • Pyrimidines / chemistry*
  • Pyrimidines / pharmacokinetics
  • Pyrimidines / pharmacology*
  • Pyrimidines / therapeutic use
  • Rats
  • Uracil / analogs & derivatives
  • Uracil / chemistry

Substances

  • Blood Glucose
  • Dipeptidyl-Peptidase IV Inhibitors
  • Piperidines
  • Pyrimidines
  • thienopyrimidine
  • Uracil
  • Dipeptidyl Peptidase 4
  • alogliptin