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

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.