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Identification of Potent and Selective Retinoic Acid Receptor Gamma (RARγ) Antagonists for the Treatment of Osteoarthritis Pain Using Structure Based Drug Design

Identification of Potent and Selective Retinoic Acid Receptor Gamma (RARγ) Antagonists for the Treatment of Osteoarthritis Pain Using Structure Based Drug Design

Norman E Hughes, Thomas J Bleisch, Scott A Jones, Timothy I Richardson, Robert A Doti, Yong Wang, Stephanie L Stout, Gregory L Durst, Mark G Chambers, Jennifer L Oskins, Chaohua Lin, Lisa A Adams, Todd J Page, etc.

Bioorg Med Chem Lett. 2016 Jul 15;26(14):3274-3277.

PMID: 27261179

Abstract:

A series of triaryl pyrazoles were identified as potent pan antagonists for the retinoic acid receptors (RARs) α, β and γ. X-ray crystallography and structure-based drug design were used to improve selectivity for RARγ by targeting residue differences in the ligand binding pockets of these receptors. This resulted in the discovery of novel antagonists which maintained RARγ potency but were greater than 500-fold selective versus RARα and RARβ. The potent and selective RARγ antagonist LY2955303 demonstrated good pharmacokinetic properties and was efficacious in the MIA model of osteoarthritis-like joint pain. This compound demonstrated an improved margin to RARα-mediated adverse effects.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
AP1433497198	LY2955303		1433497-19-8	Price

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