Discovery and optimisation of 1-hydroxyimino-3,3-diphenylpropanes, a new class of orally active GPBAR1 (TGR5) agonists

Bioorg Med Chem Lett. 2013 Aug 15;23(16):4627-32. doi: 10.1016/j.bmcl.2013.06.017. Epub 2013 Jun 19.

Abstract

A series of non-steroidal GPBAR1 (TGR5) agonists was developed from a hit in a high-throughput screening campaign. Lead identification efforts produced biphenyl-4-carboxylic acid derivative (R)-22, which displayed a robust secretion of PYY after oral administration in a degree that can be correlated with the unbound plasma concentration. Further optimisation work focusing on reduction of the lipophilicity provided the 1-phenylpiperidine-4-carboxylic acid derivative (R)-29 (RO5527239), which showed an improved secretion of PYY and GLP-1, translating into a significant reduction of postprandial blood glucose excursion in an oral glucose tolerance test in DIO mice.

Keywords: Chemical probe; GLP-1; GPBAR1; PYY; TGR5.

MeSH terms

  • Administration, Oral
  • Animals
  • Blood Glucose / drug effects*
  • Drug Discovery*
  • Inhibitory Concentration 50
  • Mice
  • Molecular Structure
  • Oximes / chemical synthesis*
  • Oximes / chemistry
  • Oximes / pharmacology
  • Propane / analogs & derivatives*
  • Propane / blood
  • Propane / chemical synthesis
  • Propane / chemistry
  • Propane / pharmacology
  • Receptors, G-Protein-Coupled / agonists*

Substances

  • Blood Glucose
  • Oximes
  • Receptors, G-Protein-Coupled
  • Propane
  • 1,3-diphenylpropane