Novel tetrahydropyran analogs as dipeptidyl peptidase IV inhibitors: Profile of clinical candidate (2R,3S,5R)-2- (2,5-difluorophenyl)-5-(4,6-dihydropyrrolo [3,4-c]pyrazol-5-(1H)-yl)tetrahydro-2H-pyran-3-amine (23) [corrected]

Bioorg Med Chem Lett. 2013 Oct 1;23(19):5361-6. doi: 10.1016/j.bmcl.2013.07.061. Epub 2013 Aug 5.

Abstract

A series of novel tri-2,3,5-substituted tetrahydropyran analogs were synthesized and evaluated as inhibitors of dipeptidyl peptidase IV (DPP-4) for the treatment of type 2 diabetes. Optimization of the series provided inhibitors with good DPP-4 potency and selectivity over other peptidases (QPP, DPP8, and FAP). Compound 23, which is very potent, selective, efficacious in the diabetes PD model, and has an excellent pharmacokinetic profile, is selected as a clinical candidate.

Keywords: DPP-4 inhibitors; DPP-IV; Diabetes; Tetrahydropyran.

MeSH terms

  • Animals
  • Diabetes Mellitus, Type 2 / drug therapy
  • Dipeptidyl-Peptidase IV Inhibitors / chemical synthesis*
  • Dipeptidyl-Peptidase IV Inhibitors / chemistry
  • Dipeptidyl-Peptidase IV Inhibitors / pharmacology
  • Dogs
  • Enzyme Activation / drug effects
  • Glucose Tolerance Test
  • Haplorhini
  • Heterocyclic Compounds, 2-Ring / chemical synthesis*
  • Humans
  • Inhibitory Concentration 50
  • Pyrans / chemical synthesis*
  • Pyrans / chemistry
  • Pyrans / pharmacology
  • Rats
  • Stereoisomerism

Substances

  • 2-(2,5-difluorophenyl)-5-(2-(methylsulfonyl)-2,6-dihydropyrrolo(3,4-c)pyrazol-5(4H)-yl)tetrahydro-2H-pyran-3-amine
  • Dipeptidyl-Peptidase IV Inhibitors
  • Heterocyclic Compounds, 2-Ring
  • Pyrans