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

Maria B. Goncalves, Earl Clarke, Christopher Jarvis, S. Barret Kalindjian, Thomas Pitcher, John Grist, Carl Hobbs, Thomas Carlstedt, Julian Jack, Jane T. Brown, Mark Mills, Peter Mumford, Alan D. Borthwick, Jonathan P.T. Corcoran

Research output: Contribution to journalArticlepeer-review

4 Citations (Scopus)
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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.
Original languageEnglish
Pages (from-to)995-1000
Number of pages6
JournalBioorganic & medicinal chemistry letters
Volume29
Issue number8
Early online date11 Feb 2019
DOIs
Publication statusPublished - 15 Apr 2019

Keywords

  • Retinoic acid receptor, Beta agonist, SAR, Neurite outgrowth, Axon regrowth, C286

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