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
; 26(14): 3274-3277, 2016 07 15.
Article
in En
| MEDLINE
| ID: mdl-27261179
ABSTRACT
A series of triaryl pyrazoles were identified as potent pan antagonists for the retinoic acid receptors (RARs) α, ß 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 RARß. 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.
Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Osteoarthritis
/
Pain
/
Piperazines
/
Pyrazoles
/
Drug Design
/
Receptors, Retinoic Acid
Type of study:
Diagnostic_studies
Limits:
Humans
Language:
En
Journal:
Bioorg Med Chem Lett
Journal subject:
BIOQUIMICA
/
QUIMICA
Year:
2016
Document type:
Article
Affiliation country:
United States