Discovery of a potent, orally available, and isoform-selective retinoic acid beta2 receptor agonist.
4'-Octyl-4-biphenylcarboxylic acid (1g, AC-55649) was identified as a highly isoform-selective agonist at the human RARbeta2 receptor in a functional intact cell-based screening assay. The subsequent hit to lead optimization transformed the lipophilic, poorly soluble hit into a more potent and orally available compound (2, AC-261066) with retained beta2 selectivity and greatly improved physiochemical properties. Being an isoform-selective RARbeta2 receptor agonist that discriminates between nuclear receptor isoforms having identical ligand binding domains, 2 will be useful as a pharmacological research tool but also a valuable starting point for drug development.
Lund
Birgitte W
BW
ACADIA Pharmaceuticals AB, Medeon Science Park, S-205 12 Malmö, Sweden.
Piu
Fabrice
F
Gauthier
Natalie K
NK
Eeg
Anne
A
Currier
Erika
E
Sherbukhin
Vladimir
V
Brann
Mark R
MR
Hacksell
Uli
U
Olsson
Roger
R
D000284:Administration, Oral; D000818:Animals; D001565:Benzoates / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001665:Binding Sites; D001682:Biological Availability; D001713:Biphenyl Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D002478:Cells, Cultured; D006801:Humans; D008958:Models, Molecular; D020033:Protein Isoforms / Q000819:agonists; D017434:Protein Structure, Tertiary; D051381:Rats; D018168:Receptors, Retinoic Acid / Q000819:agonists*; D012995:Solubility; D013329:Structure-Activity Relationship; D013844:Thiazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D014158:Transcription, Genetic
C507710:4'-octyl-4-biphenylcarboxylic acid; C507711:4-(4-(2-(n-butoxy)ethoxy)-5-methylthiazol-2-yl)-2-fluorobenzoic acid; D001565:Benzoates; D001713:Biphenyl Compounds; D020033:Protein Isoforms; D018168:Receptors, Retinoic Acid; D013844:Thiazoles; C082925:retinoic acid receptor beta