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.
Maria B Goncalves  1 ,  Earl Clarke  1 ,  Christopher I Jarvis  1 ,  S Barret Kalindjian  1 ,  Thomas Pitcher  1 ,  John Grist  1 ,  Carl Hobbs  1 ,  Thomas Carlstedt  1 ,  Julian Jack  1 ,  Jane T Brown  2 ,  Mark Mills  2 ,  Peter Mumford  2 ,  Alan D Borthwick  3 ,  Jonathan P T Corcoran  4
Affiliations
  • 1. Neuroscience Drug Discovery Unit, Wolfson Centre for Age-Related Diseases, Guy's Campus, King's College, London SE1 1UL, UK.
  • 2. Sygnature Discovery Limited, Biocity, Pennyfoot Street, Nottingham NG1 1GF, UK.
  • 3. DrugMolDesign, 15 Temple Grove, London NW11 7UA, UK. Electronic address: [email protected].
  • 4. Neuroscience Drug Discovery Unit, Wolfson Centre for Age-Related Diseases, Guy's Campus, King's College, London SE1 1UL, UK. Electronic address: [email protected].
PMID: 30792038 DOI: 10.1016/j.bmcl.2019.02.011
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.