Identification of potent and selective retinoic acid receptor gamma (RARγ) antagonists for the treatment of osteoarthritis pain using structure based drug design.
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.
Discovery Chemistry Research and Technologies, Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN 46285, United States.
Norman E
NE
Hughes
Discovery Chemistry Research and Technologies, Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN 46285, United States.
Thomas J
TJ
Bleisch
Discovery Chemistry Research and Technologies, Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN 46285, United States.
Scott A
SA
Jones
Discovery Chemistry Research and Technologies, Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN 46285, United States.
Timothy I
TI
Richardson
Discovery Chemistry Research and Technologies, Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN 46285, United States.
Robert A
RA
Doti
Discovery Chemistry Research and Technologies, Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN 46285, United States.
Yong
Y
Wang
Discovery Chemistry Research and Technologies, Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN 46285, United States.
Stephanie L
SL
Stout
Discovery Chemistry Research and Technologies, Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN 46285, United States.
Gregory L
GL
Durst
Musculoskeletal Research, Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN 46285, United States.
Mark G
MG
Chambers
Musculoskeletal Research, Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN 46285, United States.
Jennifer L
JL
Oskins
Musculoskeletal Research, Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN 46285, United States.
Chaohua
C
Lin
Toxicology/Drug Disposition, Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN 46285, United States.
Lisa A
LA
Adams
Toxicology/Drug Disposition, Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN 46285, United States.
Todd J
TJ
Page
Discovery Chemistry Research and Technologies, Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN 46285, United States.
Robert J
RJ
Barr
Discovery Chemistry Research and Technologies, Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN 46285, United States.
Richard W
RW
Zink
Discovery Chemistry Research and Technologies, Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN 46285, United States.
Harold
H
Osborne
Discovery Chemistry Research and Technologies, Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN 46285, United States.
Chahrzad
C
Montrose-Rafizadeh
Discovery Chemistry Research and Technologies, Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN 46285, United States. Electronic address: norman@lilly.com.
Bryan H
BH
Norman
D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D006801:Humans; D008958:Models, Molecular; D015394:Molecular Structure; D010003:Osteoarthritis / Q000188:drug therapy*; D010146:Pain / Q000188:drug therapy*; D010879:Piperazines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D011720:Pyrazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D018168:Receptors, Retinoic Acid / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship; D000097768:Retinoic Acid Receptor gamma
D010879:Piperazines; D011720:Pyrazoles; D018168:Receptors, Retinoic Acid; D000097768:Retinoic Acid Receptor gamma; C000621330:LY2955303
Antagonist; Osteoarthritis; Pain; RARγ; Retinoic acid receptor