7-Oxopyrrolopyridine-derived DPP4 inhibitors-mitigation of CYP and hERG liabilities via introduction of polar functionalities in the active site

Bioorg Med Chem Lett. 2011 Nov 15;21(22):6646-51. doi: 10.1016/j.bmcl.2011.09.074. Epub 2011 Sep 24.

Abstract

Design, synthesis, and SAR of 7-oxopyrrolopyridine-derived DPP4 inhibitors are described. The preferred stereochemistry of these atropisomeric biaryl analogs has been identified as Sa. Compound (+)-3t, with a K(i) against DPP4, DPP8, and DPP9 of 0.37 nM, 2.2, and 5.7 μM, respectively, showed a significant improvement in insulin response after single doses of 3 and 10 μmol/kg in ob/ob mice.

MeSH terms

  • Animals
  • Catalytic Domain
  • Cytochrome P-450 CYP3A / metabolism*
  • Diabetes Mellitus / drug therapy
  • Dipeptidyl Peptidase 4 / metabolism*
  • Dipeptidyl-Peptidase IV Inhibitors / chemistry*
  • Dipeptidyl-Peptidase IV Inhibitors / pharmacokinetics
  • Dipeptidyl-Peptidase IV Inhibitors / pharmacology*
  • Ether-A-Go-Go Potassium Channels / metabolism*
  • Humans
  • Insulin / blood
  • Insulin / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Models, Molecular
  • Pyridines / chemistry*
  • Pyridines / pharmacokinetics
  • Pyridines / pharmacology*
  • Pyrroles / chemistry
  • Pyrroles / pharmacokinetics
  • Pyrroles / pharmacology
  • Rats
  • Stereoisomerism

Substances

  • Dipeptidyl-Peptidase IV Inhibitors
  • Ether-A-Go-Go Potassium Channels
  • Insulin
  • Pyridines
  • Pyrroles
  • Cytochrome P-450 CYP3A
  • Dipeptidyl Peptidase 4