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

Maria B. Goncalves; Earl Clarke; Christopher Jarvis; S. Barret Kalindjian; Thomas Pitcher; John Grist; Carl Hobbs; Thomas Carlstedt; Julian Jack; Jane T. Brown; Mark Mills; Peter Mumford; Alan D. Borthwick; Jonathan P.T. Corcoran

doi:10.1016/j.bmcl.2019.02.011

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

Maria B. Goncalves, Earl Clarke, Christopher Jarvis, S. Barret Kalindjian, Thomas Pitcher, John Grist, Carl Hobbs, Thomas Carlstedt, Julian Jack, Jane T. Brown, Mark Mills, Peter Mumford, Alan D. Borthwick, Jonathan P.T. Corcoran

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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.

Original language	English
Pages (from-to)	995-1000
Number of pages	6
Journal	Bioorganic & medicinal chemistry letters
Volume	29
Issue number	8
Early online date	11 Feb 2019
DOIs	https://doi.org/10.1016/j.bmcl.2019.02.011
Publication status	Published - 15 Apr 2019

Keywords

Retinoic acid receptor, Beta agonist, SAR, Neurite outgrowth, Axon regrowth, C286

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10.1016/j.bmcl.2019.02.011Licence: CC BY

Discovery and lead optimisation_GONCALVES_Accepted10February2019_GOLD VoR (CC BY)Accepted author manuscript, 904 KB

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Goncalves, M. B., Clarke, E., Jarvis, C., Kalindjian, S. B., Pitcher, T., Grist, J., Hobbs, C., Carlstedt, T., Jack, J., Brown, J. T., Mills, M., Mumford, P., Borthwick, A. D., & Corcoran, J. P. T. (2019). Discovery and lead optimisation of a potent, selective and orally bioavailable RARβ agonist for the potential treatment of nerve injury. Bioorganic & medicinal chemistry letters, 29(8), 995-1000. https://doi.org/10.1016/j.bmcl.2019.02.011

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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.",

keywords = "Retinoic acid receptor, Beta agonist, SAR, Neurite outgrowth, Axon regrowth, C286",

author = "Goncalves, {Maria B.} and Earl Clarke and Christopher Jarvis and Kalindjian, {S. Barret} and Thomas Pitcher and John Grist and Carl Hobbs and Thomas Carlstedt and Julian Jack and Brown, {Jane T.} and Mark Mills and Peter Mumford and Borthwick, {Alan D.} and Corcoran, {Jonathan P.T.}",

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Goncalves, MB, Clarke, E , Jarvis, C , Kalindjian, SB , Pitcher, T, Grist, J, Hobbs, C, Carlstedt, T, Jack, J, Brown, JT, Mills, M, Mumford, P, Borthwick, AD & Corcoran, JPT 2019, 'Discovery and lead optimisation of a potent, selective and orally bioavailable RARβ agonist for the potential treatment of nerve injury', Bioorganic & medicinal chemistry letters, vol. 29, no. 8, pp. 995-1000. https://doi.org/10.1016/j.bmcl.2019.02.011

TY - JOUR

T1 - Discovery and lead optimisation of a potent, selective and orally bioavailable RARβ agonist for the potential treatment of nerve injury

AU - Goncalves, Maria B.

AU - Clarke, Earl

AU - Jarvis, Christopher

AU - Kalindjian, S. Barret

AU - Pitcher, Thomas

AU - Grist, John

AU - Hobbs, Carl

AU - Carlstedt, Thomas

AU - Jack, Julian

AU - Brown, Jane T.

AU - Mills, Mark

AU - Mumford, Peter

AU - Borthwick, Alan D.

AU - Corcoran, Jonathan P.T.

PY - 2019/4/15

Y1 - 2019/4/15

N2 - 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.

AB - 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.

KW - Retinoic acid receptor, Beta agonist, SAR, Neurite outgrowth, Axon regrowth, C286

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DO - 10.1016/j.bmcl.2019.02.011

M3 - Article

SN - 0960-894X

VL - 29

SP - 995

EP - 1000

JO - Bioorganic & medicinal chemistry letters

JF - Bioorganic & medicinal chemistry letters

IS - 8

ER -

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

Abstract

Keywords

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