Discovery and lead optimisation of a potent, selective and orally bioavailable RARβ agonist for the potential treatment of nerve injury. Issue 8 (15th April 2019)

• Record Type: Journal Article
• Authors: Goncalves, Maria B.; Clarke, Earl; Jarvis, Christopher I.; Barret Kalindjian, S.; Pitcher, Thomas; Grist, John; Hobbs, Carl; Carlstedt, Thomas; Jack, Julian; Brown, Jane T.; Mills, Mark; Mumford, Peter; Borthwick, Alan D.; Corcoran, Jonathan P.T.
• Is Part Of: Bioorganic & medicinal chemistry letters. Volume 29:Issue 8(2019)
• Page Start: 995
• Page End: 1000
• Publication Date: 2019-04-15
• Subjects: Retinoic acid receptor -- Beta agonist -- SAR -- Neurite outgrowth -- Axon regrowth -- C286; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; 572
• DOI: 10.1016/j.bmcl.2019.02.011
• Languages: English
• ISSNs: 0960-894X

Abstract

Graphical abstract: 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.