Discovery and lead optimisation of a potent, selective and orally bioavailable RARβ agonist for the potential treatment of nerve injury

Bioorg Med Chem Lett. 2019 Apr 15;29(8):995-1000. doi: 10.1016/j.bmcl.2019.02.011. Epub 2019 Feb 11.

Abstract

Oxadiazole replacement of an amide linkage in an RARα agonist template 1, followed by lead optimisation, has produced a highly potent and selective RARβ agonist 4-(5-(4,7-dimethylbenzofuran-2-yl)-1,2,4-oxadiazol-3-yl)benzoic acid (10) with good oral bioavailability in the rat and dog. This molecule increases neurite outgrowth in vitro and induces sensory axon regrowth in vivo in a rodent model of avulsion and crush injury, and thus has the potential for the treatment of nerve injury.

Keywords: Axon regrowth; Beta agonist; C286; Neurite outgrowth; Retinoic acid receptor; SAR.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Administration, Oral
  • Animals
  • Dogs
  • Drug Evaluation, Preclinical
  • Half-Life
  • Locomotion / drug effects
  • Madin Darby Canine Kidney Cells
  • Neuronal Outgrowth / drug effects
  • Optic Nerve Injuries / drug therapy
  • Oxadiazoles / chemistry*
  • Oxadiazoles / pharmacokinetics
  • Oxadiazoles / pharmacology
  • Rats
  • Receptors, Retinoic Acid / agonists*
  • Receptors, Retinoic Acid / metabolism
  • Structure-Activity Relationship

Substances

  • Oxadiazoles
  • Receptors, Retinoic Acid
  • retinoic acid receptor beta