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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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
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author 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.
author_facet 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.
author_sort Goncalves, Maria B.
collection PubMed
description 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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spelling pubmed-64195712019-04-15 Discovery and lead optimisation of a potent, selective and orally bioavailable RARβ agonist for the potential treatment of nerve injury 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. Bioorg Med Chem Lett Article 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. Elsevier Science Ltd 2019-04-15 /pmc/articles/PMC6419571/ /pubmed/30792038 http://dx.doi.org/10.1016/j.bmcl.2019.02.011 Text en © 2019 The Authors http://creativecommons.org/licenses/by/4.0/ This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
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.
Discovery and lead optimisation of a potent, selective and orally bioavailable RARβ agonist for the potential treatment of nerve injury
title Discovery and lead optimisation of a potent, selective and orally bioavailable RARβ agonist for the potential treatment of nerve injury
title_full Discovery and lead optimisation of a potent, selective and orally bioavailable RARβ agonist for the potential treatment of nerve injury
title_fullStr Discovery and lead optimisation of a potent, selective and orally bioavailable RARβ agonist for the potential treatment of nerve injury
title_full_unstemmed Discovery and lead optimisation of a potent, selective and orally bioavailable RARβ agonist for the potential treatment of nerve injury
title_short Discovery and lead optimisation of a potent, selective and orally bioavailable RARβ agonist for the potential treatment of nerve injury
title_sort discovery and lead optimisation of a potent, selective and orally bioavailable rarβ agonist for the potential treatment of nerve injury
topic Article
url 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
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