Design, synthesis, and structure-activity analysis of isoform-selective retinoic acid receptor beta ligands.
We recently discovered the isoform selective RAR beta 2 ligand 4'-octyl-4-biphenylcarboxylic acid (3, AC-55649). Although 3 is highly potent at RAR beta 2 and displays excellent selectivity, solubility issues make it unsuitable for drug development. Herein we describe the exploration of the SAR in a biphenyl and a phenylthiazole series of analogues of 3. This ultimately led to the design of 28, a novel, orally available ligand with excellent isoform selectivity for the RAR beta 2.
Lund
Birgitte W
BW
ACADIA Pharmaceuticals AB, Medeon Science Park, S-205 12 Malmo, Sweden.
Knapp
Anne Eeg
AE
Piu
Fabrice
F
Gauthier
Natalie K
NK
Begtrup
Mikael
M
Hacksell
Uli
U
Olsson
Roger
R
D045744:Cell Line, Tumor; D015195:Drug Design; D006801:Humans; D008024:Ligands; D018168:Receptors, Retinoic Acid / Q000187:drug effects* / Q000378:metabolism; D013329:Structure-Activity Relationship
D008024:Ligands; D018168:Receptors, Retinoic Acid; C082925:retinoic acid receptor beta