A new class of RAR subtype selective retinoids: correlation of pharmacological effects with receptor activity.
The synthesis and biological activity of a series of structurally related retinoids with different RAR subtype selectivities are described. These retinoids bind to all three RAR subtypes but in functional transactivation assays, they show RARbeta or RARbeta,gamma selectivity with weak RARalpha activity. The subtype selectivity of these retinoids was found to correlate with their efficacy (ODC inhibition) and toxicity (topical irritation and teratogenicity) profiles. The degree of RARgamma transactivation activity correlates with their topical toxicity and teratogenicity as measured by the inhibition of chondrogenesis. Of the RARbeta selective retinoids reported here, retinoid 12 is the most promising, as it is completely devoid of two common retinoid related toxicities, namely topical irritation and teratogenesis.
Vuligonda
V
V
Department of Chemistry, Retinoid Research, Allergan Inc., Irvine, CA 92614, USA.
Lin
Y
Y
Thacher
S M
SM
Standeven
A M
AM
Kochar
D M
DM
Chandraratna
R A
RA
D000818:Animals; D002478:Cells, Cultured; D020219:Chondrogenesis / Q000187:drug effects; D002855:Chromatography, Thin Layer; D004305:Dose-Response Relationship, Drug; D004622:Embryo, Mammalian / Q000187:drug effects; D020128:Inhibitory Concentration 50; D007700:Kinetics; D008156:Luciferases / Q000378:metabolism; D009682:Magnetic Resonance Spectroscopy; D051379:Mice; D008812:Mice, Hairless; D008956:Models, Chemical; D011485:Protein Binding; D018168:Receptors, Retinoic Acid / Q000145:classification* / Q000378:metabolism*; D000072482:Retinoic Acid Receptor alpha; D012176:Retinoids / Q000138:chemical synthesis* / Q000145:classification*; D014162:Transfection; D000097768:Retinoic Acid Receptor gamma
D008156:Luciferases; D018168:Receptors, Retinoic Acid; D000072482:Retinoic Acid Receptor alpha; D012176:Retinoids; D000097768:Retinoic Acid Receptor gamma; C000607072:Rara protein, mouse; C082925:retinoic acid receptor beta