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

[Display omitted] 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 rece...

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Bibliographic Details
Published in:Bioorganic & medicinal chemistry 2018-02, Vol.26 (4), p.798-814
Main Authors: Clarke, Earl, Jarvis, Christopher I., Goncalves, Maria B., Kalindjian, S. Barret, Adams, David R., Brown, Jane T., Shiers, Jason J., Taddei, David M.A., Ravier, Elodie, Barlow, Stephanie, Miller, Iain, Smith, Vanessa, Borthwick, Alan D., Corcoran, Jonathan P.T.
Format: Article
Language:English
Subjects:
Administration, Oral
Aminobenzoates - chemistry
Aminobenzoates - pharmacokinetics
Aminobenzoates - toxicity
Animals
Benzoates - chemistry
Benzoates - pharmacokinetics
Benzoates - toxicity
Cell Survival - drug effects
Chlorocebus aethiops
COS Cells
Drug Design
Half-Life
Hep G2 Cells
Humans
Mice
Microsomes, Liver - metabolism
Rats
Receptors, Retinoic Acid - agonists
Receptors, Retinoic Acid - metabolism
Retinoic Acid Receptor alpha - agonists
Retinoic Acid Receptor alpha - metabolism
Retinoic Acid Receptor gamma
Structure-Activity Relationship
Tetrahydronaphthalenes - chemistry
Tetrahydronaphthalenes - pharmacokinetics
Tetrahydronaphthalenes - toxicity
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Summary:[Display omitted] 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.
ISSN:0968-0896
1464-3391
DOI:10.1016/j.bmc.2017.12.015