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 r etinoids with different RAR subtype selectivities are described. These reti noids bind to all three RAR subtypes but in functional transactivation assa ys, they show RAR beta or RAR beta,gamma selectivity with weak RAR alpha ac tivity. The subtype selectivity of these retinoids was found to correlate w ith their efficacy (ODC inhibition) and toxicity (topical irritation and te ratogenicity) profiles. The degree of RAR gamma transactivation activity co rrelates with their topical toxicity and teratogenicity as measured by the inhibition of chondrogenesis. Of the RAR beta 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 teratogen esis. (C) 1999 Elsevier Science Ltd. All rights reserved.