title: Design, synthesis, and structure-activity analysis of isoform-selective retinoic acid receptor beta ligands.
abstract: 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.
authors.affiliation: ACADIA Pharmaceuticals AB, Medeon Science Park, S-205 12 Malmo, Sweden.
authors.forename: Birgitte W
authors.initials: BW
authors.lastname: Lund
authors.forename: Anne Eeg
authors.initials: AE
authors.lastname: Knapp
authors.forename: Fabrice
authors.initials: F
authors.lastname: Piu
authors.forename: Natalie K
authors.initials: NK
authors.lastname: Gauthier
authors.forename: Mikael
authors.initials: M
authors.lastname: Begtrup
authors.forename: Uli
authors.initials: U
authors.lastname: Hacksell
authors.forename: Roger
authors.initials: R
authors.lastname: Olsson
mesh_terms: D045744:Cell Line, Tumor; D015195:Drug Design; D006801:Humans; D008024:Ligands; D018168:Receptors, Retinoic Acid / Q000187:drug effects* / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D008024:Ligands; D018168:Receptors, Retinoic Acid; C082925:retinoic acid receptor beta