Design and synthesis of a potent, highly selective, orally bioavailable, retinoic acid receptor alpha agonist

Earl Clarke; Christopher I. Jarvis; Maria B. Goncalves; S. Barret Kalindjian; David R. Adams; Jane T. Brown; Jason J. Shiers; David M.A. Taddei; Elodie Ravier; Stephanie Barlow; Iain Miller; Vanessa Smith; Alan D. Borthwick; Jonathan P.T. Corcoran

doi:10.1016/j.bmc.2017.12.015

Design and synthesis of a potent, highly selective, orally bioavailable, retinoic acid receptor alpha agonist

Earl Clarke, Christopher I. Jarvis, Maria B. Goncalves, S. Barret Kalindjian, David R. Adams, Jane T. Brown, Jason J. Shiers, David M.A. Taddei, Elodie Ravier, Stephanie Barlow, Iain Miller, Vanessa Smith, Alan D. Borthwick, Jonathan P.T. Corcoran

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Abstract

A ligand-based virtual screening exercise examining likely bioactive conformations of AM 580 (2) and AGN 193836 (3) was used to identify the novel, less lipophilic RARα agonist 4-(3,5-dichloro-4-ethoxybenzamido)benzoic acid 5, which has good selectivity over the RARβ, and RARγ receptors. Analysis of the medicinal chemistry parameters of the 3,5-substituents of derivatives of template 5 enabled us to design a class of drug-like molecules with lower intrinsic clearance and higher oral bioavailability which led to the novel RARα agonist 4-(3-chloro-4-ethoxy-5-isopropoxybenzamido)-2-methylbenzoic acid 56 that has high RARα potency and excellent selectivity versus RARβ (2 orders of magnitude) and RARγ (4 orders of magnitude) at both the human and mouse RAR receptors with improved drug-like properties. This RARα specific agonist 56 has high oral bioavailability (>80%) in both mice and dogs with a good PK profile and was shown to be inactive in cytotoxicity and genotoxicity screens.

Original language	English
Journal	Bioorganic and Medicinal Chemistry
Early online date	9 Dec 2017
DOIs	https://doi.org/10.1016/j.bmc.2017.12.015
Publication status	E-pub ahead of print - 9 Dec 2017

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10.1016/j.bmc.2017.12.015

Design and synthesis of_CLARKE_Publishedonline9December2017_GREEN AAM (CC BY-NC-ND)Accepted author manuscript, 650 KBLicence: CC BY-NC-ND

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Clarke, E., Jarvis, C. I., Goncalves, M. B., Kalindjian, S. B., Adams, D. R., Brown, J. T., Shiers, J. J., Taddei, D. M. A., Ravier, E., Barlow, S., Miller, I., Smith, V., Borthwick, A. D., & Corcoran, J. P. T. (2017). Design and synthesis of a potent, highly selective, orally bioavailable, retinoic acid receptor alpha agonist. Bioorganic and Medicinal Chemistry. Advance online publication. https://doi.org/10.1016/j.bmc.2017.12.015

@article{1fc9f7b723dd47c8835b238569470eba,

title = "Design and synthesis of a potent, highly selective, orally bioavailable, retinoic acid receptor alpha agonist",

abstract = "A ligand-based virtual screening exercise examining likely bioactive conformations of AM 580 (2) and AGN 193836 (3) was used to identify the novel, less lipophilic RARα agonist 4-(3,5-dichloro-4-ethoxybenzamido)benzoic acid 5, which has good selectivity over the RARβ, and RARγ receptors. Analysis of the medicinal chemistry parameters of the 3,5-substituents of derivatives of template 5 enabled us to design a class of drug-like molecules with lower intrinsic clearance and higher oral bioavailability which led to the novel RARα agonist 4-(3-chloro-4-ethoxy-5-isopropoxybenzamido)-2-methylbenzoic acid 56 that has high RARα potency and excellent selectivity versus RARβ (2 orders of magnitude) and RARγ (4 orders of magnitude) at both the human and mouse RAR receptors with improved drug-like properties. This RARα specific agonist 56 has high oral bioavailability (>80%) in both mice and dogs with a good PK profile and was shown to be inactive in cytotoxicity and genotoxicity screens.",

author = "Earl Clarke and Jarvis, {Christopher I.} and Goncalves, {Maria B.} and Kalindjian, {S. Barret} and Adams, {David R.} and Brown, {Jane T.} and Shiers, {Jason J.} and Taddei, {David M.A.} and Elodie Ravier and Stephanie Barlow and Iain Miller and Vanessa Smith and Borthwick, {Alan D.} and Corcoran, {Jonathan P.T.}",

year = "2017",

month = dec,

day = "9",

doi = "10.1016/j.bmc.2017.12.015",

language = "English",

journal = "Bioorganic and Medicinal Chemistry",

issn = "0968-0896",

publisher = "Elsevier Limited",

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Clarke, E , Jarvis, CI , Goncalves, MB , Kalindjian, SB, Adams, DR, Brown, JT, Shiers, JJ, Taddei, DMA, Ravier, E, Barlow, S, Miller, I, Smith, V, Borthwick, AD & Corcoran, JPT 2017, 'Design and synthesis of a potent, highly selective, orally bioavailable, retinoic acid receptor alpha agonist', Bioorganic and Medicinal Chemistry. https://doi.org/10.1016/j.bmc.2017.12.015

TY - JOUR

T1 - Design and synthesis of a potent, highly selective, orally bioavailable, retinoic acid receptor alpha agonist

AU - Clarke, Earl

AU - Jarvis, Christopher I.

AU - Goncalves, Maria B.

AU - Kalindjian, S. Barret

AU - Adams, David R.

AU - Brown, Jane T.

AU - Shiers, Jason J.

AU - Taddei, David M.A.

AU - Ravier, Elodie

AU - Barlow, Stephanie

AU - Miller, Iain

AU - Smith, Vanessa

AU - Borthwick, Alan D.

AU - Corcoran, Jonathan P.T.

PY - 2017/12/9

Y1 - 2017/12/9

N2 - A ligand-based virtual screening exercise examining likely bioactive conformations of AM 580 (2) and AGN 193836 (3) was used to identify the novel, less lipophilic RARα agonist 4-(3,5-dichloro-4-ethoxybenzamido)benzoic acid 5, which has good selectivity over the RARβ, and RARγ receptors. Analysis of the medicinal chemistry parameters of the 3,5-substituents of derivatives of template 5 enabled us to design a class of drug-like molecules with lower intrinsic clearance and higher oral bioavailability which led to the novel RARα agonist 4-(3-chloro-4-ethoxy-5-isopropoxybenzamido)-2-methylbenzoic acid 56 that has high RARα potency and excellent selectivity versus RARβ (2 orders of magnitude) and RARγ (4 orders of magnitude) at both the human and mouse RAR receptors with improved drug-like properties. This RARα specific agonist 56 has high oral bioavailability (>80%) in both mice and dogs with a good PK profile and was shown to be inactive in cytotoxicity and genotoxicity screens.

AB - A ligand-based virtual screening exercise examining likely bioactive conformations of AM 580 (2) and AGN 193836 (3) was used to identify the novel, less lipophilic RARα agonist 4-(3,5-dichloro-4-ethoxybenzamido)benzoic acid 5, which has good selectivity over the RARβ, and RARγ receptors. Analysis of the medicinal chemistry parameters of the 3,5-substituents of derivatives of template 5 enabled us to design a class of drug-like molecules with lower intrinsic clearance and higher oral bioavailability which led to the novel RARα agonist 4-(3-chloro-4-ethoxy-5-isopropoxybenzamido)-2-methylbenzoic acid 56 that has high RARα potency and excellent selectivity versus RARβ (2 orders of magnitude) and RARγ (4 orders of magnitude) at both the human and mouse RAR receptors with improved drug-like properties. This RARα specific agonist 56 has high oral bioavailability (>80%) in both mice and dogs with a good PK profile and was shown to be inactive in cytotoxicity and genotoxicity screens.

U2 - 10.1016/j.bmc.2017.12.015

DO - 10.1016/j.bmc.2017.12.015

M3 - Article

SN - 0968-0896

JO - Bioorganic and Medicinal Chemistry

JF - Bioorganic and Medicinal Chemistry

ER -

Design and synthesis of a potent, highly selective, orally bioavailable, retinoic acid receptor alpha agonist

Abstract

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