Discovery of XL335 (WAY-362450), a highly potent, selective, and orally active agonist of the farnesoid X receptor (FXR)

J Med Chem. 2009 Feb 26;52(4):904-7. doi: 10.1021/jm8014124.

Abstract

Azepino[4,5-b]indoles have been identified as potent agonists of the farnesoid X receptor (FXR). In vitro and in vivo optimization has led to the discovery of 6m (XL335, WAY-362450) as a potent, selective, and orally bioavailable FXR agonist (EC(50) = 4 nM, Eff = 149%). Oral administration of 6m to LDLR(-/-) mice results in lowering of cholesterol and triglycerides. Chronic administration in an atherosclerosis model results in significant reduction in aortic arch lesions.

MeSH terms

  • Administration, Oral
  • Animals
  • Aorta, Thoracic / pathology
  • Atherosclerosis / drug therapy*
  • Atherosclerosis / prevention & control
  • Azepines / pharmacokinetics
  • Azepines / pharmacology*
  • Azepines / therapeutic use
  • Cholesterol / blood
  • DNA-Binding Proteins / agonists*
  • Disease Models, Animal
  • Drug Discovery
  • Indoles / pharmacokinetics
  • Indoles / pharmacology*
  • Indoles / therapeutic use
  • Mice
  • Mice, Knockout
  • Receptors, Cytoplasmic and Nuclear / agonists*
  • Receptors, LDL / deficiency
  • Transcription Factors / agonists*
  • Triglycerides / blood

Substances

  • Azepines
  • DNA-Binding Proteins
  • Indoles
  • Receptors, Cytoplasmic and Nuclear
  • Receptors, LDL
  • Transcription Factors
  • Triglycerides
  • WAY-362450
  • farnesoid X-activated receptor
  • Cholesterol