[Discovery of a Potent, Orally Available, and Isoform-Selective Retinoic Acid beta2 Receptor Agonist]
>>J Med Chem. 2005 Dec 1;48(24):7517-9.
Discovery of a Potent, Orally Available, and Isoform-Selective Retinoic Acid beta2 Receptor Agonist.
Lund BW, Piu F, Gauthier NK, Eeg A, Currier E, Sherbukhin V, Brann MR, Hacksell U, Olsson R.
ACADIA Pharmaceuticals AB, Medeon Science Park, S-205 12 Malmo, Sweden, and ACADIA Pharmaceuticals Inc., 3911 Sorrento Valley Blvd., San Diego, California 92121.
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.<<
Cheers, Tuck |
