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

ABSTRACT: Oxadiazole replacement of an amide linkage in an RAR? agonist template 1, followed by lead optimisation, has produced a highly potent and selective RAR? 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.

SUBMITTER: Goncalves MB

PROVIDER: S-EPMC6419571 | biostudies-literature | 2019 Apr

REPOSITORIES: biostudies-literature

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

Goncalves Maria B MB Clarke Earl E Jarvis Christopher I CI Barret Kalindjian S S Pitcher Thomas T Grist John J Hobbs Carl C Carlstedt Thomas T Jack Julian J Brown Jane T JT Mills Mark M Mumford Peter P Borthwick Alan D AD Corcoran Jonathan P T JPT

Bioorganic & medicinal chemistry letters 20190211 8

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. ...[more]

PMID: 30792038

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