Optimization of activity, selectivity, and liability profiles in 5-oxopyrrolopyridine DPP4 inhibitors leading to clinical candidate (Sa)-2-(3-(aminomethyl)-4-(2,4-dichlorophenyl)-2-methyl-5-oxo-5H-pyrrolo[3,4-b]pyridin-6(7H)-yl)-N,N-dimethylacetamide (BMS-767778)

J Med Chem. 2013 Sep 26;56(18):7343-57. doi: 10.1021/jm4008906. Epub 2013 Sep 9.

Abstract

Optimization of a 5-oxopyrrolopyridine series based upon structure-activity relationships (SARs) developed from our previous efforts on a number of related bicyclic series yielded compound 2s (BMS-767778) with an overall activity, selectivity, efficacy, PK, and developability profile suitable for progression into the clinic. SAR in the series and characterization of 2s are described.

MeSH terms

  • Acetamides / chemical synthesis
  • Acetamides / chemistry*
  • Acetamides / pharmacology*
  • Animals
  • Bridged Bicyclo Compounds, Heterocyclic / chemical synthesis
  • Bridged Bicyclo Compounds, Heterocyclic / chemistry*
  • Bridged Bicyclo Compounds, Heterocyclic / pharmacology*
  • Catalytic Domain
  • Dipeptidyl Peptidase 4 / chemistry
  • Dipeptidyl Peptidase 4 / metabolism*
  • Dipeptidyl-Peptidase IV Inhibitors / chemical synthesis
  • Dipeptidyl-Peptidase IV Inhibitors / chemistry*
  • Dipeptidyl-Peptidase IV Inhibitors / pharmacology*
  • Drug Design*
  • Glucose Tolerance Test
  • Humans
  • Male
  • Mice
  • Models, Molecular
  • Pyrroles / chemical synthesis
  • Pyrroles / chemistry*
  • Pyrroles / pharmacology*
  • Substrate Specificity

Substances

  • 2-(3-(aminomethyl)-4-(2,4-dichlorophenyl)-2-methyl-5-oxo-5H-pyrrolo(3,4-b)pyridin-6(7H)-yl)-N,N-dimethylacetamide
  • Acetamides
  • Bridged Bicyclo Compounds, Heterocyclic
  • Dipeptidyl-Peptidase IV Inhibitors
  • Pyrroles
  • Dipeptidyl Peptidase 4