From partial to full agonism: identification of a novel 2,4,5,6-tetrahydropyrrolo[3,4-c]pyrazole as a full agonist of the human GPR119 receptor

Bioorg Med Chem Lett. 2013 Jan 1;23(1):194-7. doi: 10.1016/j.bmcl.2012.10.119. Epub 2012 Nov 5.

Abstract

A novel GPR119 agonist based on the 2,4,5,6-tetrahydropyrrolo[3,4-c]pyrazole scaffold was designed through lead optimization starting from pyrazole-based GPR119 agonist 1. The design is centered on the conformational restriction of the core scaffold, while minimizing the change in spatial relationships of two key pharmacophoric elements (piperidine-carbamate and aryl sulfone).

MeSH terms

  • Carbamates / chemistry
  • Humans
  • Piperidines / chemistry
  • Protein Binding
  • Pyrazoles / chemical synthesis
  • Pyrazoles / chemistry*
  • Pyrazoles / metabolism
  • Receptors, G-Protein-Coupled / agonists*
  • Receptors, G-Protein-Coupled / metabolism
  • Structure-Activity Relationship

Substances

  • Carbamates
  • GPR119 protein, human
  • Piperidines
  • Pyrazoles
  • Receptors, G-Protein-Coupled
  • pyrazole
  • piperidine