The discovery of novel 5,6,5- and 5,5,6-tricyclic pyrrolidines as potent and selective DPP-4 inhibitors

Bioorg Med Chem Lett. 2016 Jun 1;26(11):2622-6. doi: 10.1016/j.bmcl.2016.04.020. Epub 2016 Apr 9.

Abstract

Novel potent and selective 5,6,5- and 5,5,6-tricyclic pyrrolidine dipeptidyl peptidase IV (DPP-4) inhibitors were identified. Structure-activity relationship (SAR) efforts focused on improving the intrinsic DPP-4 inhibition potency, increasing protease selectivity, and demonstrating clean ion channel and cytochrome P450 profiles while trying to achieve a pharmacokinetic profile suitable for once weekly dosing in humans.

Keywords: Dipeptidyl peptidase IV (DPP-4); Omarigliptin; Sitagliptin; Type 2 diabetes mellitus.

MeSH terms

  • Animals
  • Crystallography, X-Ray
  • Dipeptidyl Peptidase 4 / metabolism*
  • Dipeptidyl-Peptidase IV Inhibitors / chemical synthesis
  • Dipeptidyl-Peptidase IV Inhibitors / chemistry
  • Dipeptidyl-Peptidase IV Inhibitors / pharmacology*
  • Dogs
  • Dose-Response Relationship, Drug
  • Drug Discovery*
  • Humans
  • Models, Molecular
  • Molecular Structure
  • Pyrrolidines / chemical synthesis
  • Pyrrolidines / chemistry
  • Pyrrolidines / pharmacology*
  • Rats
  • Structure-Activity Relationship

Substances

  • Dipeptidyl-Peptidase IV Inhibitors
  • Pyrrolidines
  • DPP4 protein, human
  • Dipeptidyl Peptidase 4