Design, synthesis, and evaluation of simple phenol amides as ERRγ agonists

Bioorg Med Chem Lett. 2018 May 1;28(8):1313-1319. doi: 10.1016/j.bmcl.2018.03.019. Epub 2018 Mar 8.

Abstract

Herein we report the design and synthesis of a series of simple phenol amide ERRγ agonists based on a hydrazone lead molecule. Our structure activity relationship studies in this series revealed the phenol portion of the molecule to be required for activity. Attempts to replace the hydrazone with more suitable chemotypes led to a simple amide as a viable alternative. Differential hydrogen-deuterium exchange experiments were used to help understand the structural basis for binding to ERRγ and aid in the development of more potent ligands.

Keywords: Agonist; Amide; ERRγ; Nuclear receptor; Selective ligand.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Benzamides / chemical synthesis
  • Benzamides / chemistry
  • Benzamides / pharmacology*
  • Binding Sites
  • Drug Stability
  • Estrogens / chemical synthesis
  • Estrogens / chemistry
  • Estrogens / pharmacology*
  • HEK293 Cells
  • Half-Life
  • Humans
  • Hydrazones / chemical synthesis
  • Hydrazones / chemistry
  • Hydrazones / pharmacology
  • Microsomes, Liver / metabolism
  • Molecular Structure
  • Phenols / chemical synthesis
  • Phenols / chemistry
  • Phenols / pharmacology*
  • Receptors, Estrogen / chemistry
  • Receptors, Estrogen / metabolism*
  • Structure-Activity Relationship

Substances

  • Benzamides
  • Estrogens
  • Hydrazones
  • Phenols
  • Receptors, Estrogen
  • estrogen receptor gamma