2. Academic Validation
  3. 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

  • Bioorg Med Chem Lett. 2016 Jul 15;26(14):3274-3277. doi: 10.1016/j.bmcl.2016.05.056.
Norman E Hughes 1,  Thomas J Bleisch 1,  Scott A Jones 1,  Timothy I Richardson 1,  Robert A Doti 1,  Yong Wang 1,  Stephanie L Stout 1,  Gregory L Durst 1,  Mark G Chambers 2,  Jennifer L Oskins 2,  Chaohua Lin 2,  Lisa A Adams 3,  Todd J Page 3,  Robert J Barr 1,  Richard W Zink 1,  Harold Osborne 1,  Chahrzad Montrose-Rafizadeh 1,  Bryan H Norman 4
Affiliations

Affiliations

  • 1 Discovery Chemistry Research and Technologies, Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN 46285, United States.
  • 2 Musculoskeletal Research, Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN 46285, United States.
  • 3 Toxicology/Drug Disposition, Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN 46285, United States.
  • 4 Discovery Chemistry Research and Technologies, Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN 46285, United States. Electronic address: norman@lilly.com.
PMID: 27261179 DOI: 10.1016/j.bmcl.2016.05.056
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.

Keywords

Antagonist; Osteoarthritis; Pain; RARγ; Retinoic acid receptor.

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