Design of a novel oral Retinoic Acid Receptor alpha agonist that is potent and highly selective

What is it about?

RAR alpha agonists have the therapeutic potential for the treatment of cancer, dermatological diseases, Alzheimer’s disease and immunological disorders. We have shown how to design a novel, potent, highly selective RAR alpha agonists not based on the bicyclic 5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalene class that are ligand efficient, orally bioavailable and without the lipophilic obesity seen with the known selective RAR alpha agonists. We outline here how we discovered our initial hit compound by a ligand-based virtual screening exercise and how this was developed using analysis of the medicinal chemistry parameters of the 3,5-aromatic substituents to give a orally bioavailable, highly potent RAR alpha agonist with excellent selectivity versus RAR beta (2 orders of magnitude) and RAR gamma (4 orders of magnitude) at the human RAR receptors which exhibits promising drug-like properties. It was shown to be inactive in cytotoxicity and genotoxicity screens warranting further consideration as a potential therapeutic agent.

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Why is it important?

This is the first orally bioavailable, potent, and highly selective RAR alpha agonist not based on the bicyclic 5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalene class of the known selective RAR alpha agonists that has promising drug-like properties warranting further consideration as a potential therapeutic agent.

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