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

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...

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Detalles Bibliográficos
Autores principales: 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.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Elsevier Science Ltd 2019
Materias:
Article
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6419571/
https://www.ncbi.nlm.nih.gov/pubmed/30792038
http://dx.doi.org/10.1016/j.bmcl.2019.02.011
Descripción
Sumario: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.

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