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ID: ALA3813675
Journal: Bioorg Med Chem Lett
Title: Identification of potent and selective retinoic acid receptor gamma (RARγ) antagonists for the treatment of osteoarthritis pain using structure based drug design.
Authors: Hughes NE, Bleisch TJ, Jones SA, Richardson TI, Doti RA, Wang Y, Stout SL, Durst GL, Chambers MG, Oskins JL, Lin C, Adams LA, Page TJ, Barr RJ, Zink RW, Osborne H, Montrose-Rafizadeh C, Norman BH.
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.
CiteXplore: 27261179