Retinoic acid receptor beta,gamma-selective ligands: synthesis and biological activity of 6-substituted 2-naphthoic acid retinoids.
In search for retinoic acid receptor (RAR) selective ligands, a series of 6-substituted 2-naphthoic acid retinoids were synthesized and evaluated in vitro in a transactivation assay and a competition binding assay for all RARs. These derivatives, in general, showed RAR beta,gamma selectivity. Among these naphthoic acids, oxime derivative 12 was identified as a potent RAR gamma-selective retinoid, while olefinic derivative 11 was found to be comparable to retinoic acid and slightly RAR beta,gamma selective. For the bioassays, a general correlation was observed between the binding affinity of the ligand to the receptors and the potency of the compounds in the transactivation assay. The structure-activity relationship of these naphthoic acids will be discussed.
Yu
K L
KL
Bristol-Myers Squibb Company, Pharmaceutical Research Institute, Wallingford, Connecticut 06492, USA.
Spinazze
P
P
Ostrowski
J
J
Currier
S J
SJ
Pack
E J
EJ
Hammer
L
L
Roalsvig
T
T
Honeyman
J A
JA
Tortolani
D R
DR
Reczek
P R
PR
Mansuri
M M
MM
Starrett
J E
JE
D001667:Binding, Competitive; D015195:Drug Design; D017930:Genes, Reporter; D006367:HeLa Cells / Q000187:drug effects; D006801:Humans; D008024:Ligands; D015394:Molecular Structure; D009281:Naphthalenes / Q000737:chemistry*; D018168:Receptors, Retinoic Acid / Q000187:drug effects* / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D012176:Retinoids / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D013379:Substrate Specificity; D015533:Transcriptional Activation / Q000187:drug effects; D014212:Tretinoin / Q000378:metabolism; D000097768:Retinoic Acid Receptor gamma
D008024:Ligands; D009281:Naphthalenes; D018168:Receptors, Retinoic Acid; D011993:Recombinant Fusion Proteins; D012176:Retinoids; D014212:Tretinoin; D000097768:Retinoic Acid Receptor gamma; C082925:retinoic acid receptor beta; C030037:2-naphthoic acid