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Bioorg Med Chem. 2018 Feb 15;26(4):798-814. doi: 10.1016/j.bmc.2017.12.015. Epub 2017 Dec 9.

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

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Neuroscience Drug Discovery Unit, Wolfson Centre for Age-Related Diseases, Guy's Campus, King's College, London SE1 1UL, UK.
Sygnature Discovery Limited, Biocity, Pennyfoot Street, Nottingham NG1 1GF, UK.
DrugMolDesign, 15 Temple Grove, London NW11 7UA, UK. Electronic address:


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.

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