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

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

Author information

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.

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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