2. Academic Validation
  3. Discovery and lead optimisation of a potent, selective and orally bioavailable RARβ agonist for the potential treatment of nerve injury

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

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: alan.d.borthwick@drugmoldesign.com.
  • 4 Neuroscience Drug Discovery Unit, Wolfson Centre for Age-Related Diseases, Guy's Campus, King's College, London SE1 1UL, UK. Electronic address: jonathan.corcoran@kcl.ac.uk.
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.

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