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.

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.

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The activity of retinoid receptors activity can be regulated by various extracellular stimuli. In an effort to understand the molecular basis for this phenomenon, the role of b-arrestins was investigated. b-Arrestins constitute a class of proteins involved in the internalization of agonistactivated receptors. They have also been linked to MAPK activation suggesting a direct involvement in signaling cascades. Here, we report that b-arrestin 2 stimulates the transcriptional activation of the retinoid RAR and RXR receptors. Of all the retinoid receptors, the RAR b2 subtype showed the strongest sensitivity to b-arrestin 2 action. Interestingly, this event requires the presence of the MAP kinase ERK2, but not that of JNK or P38. Sitedirected mutagenesis showed that Ser 22 and Leu 217 are critical residues of the RAR b2 receptor through which b-arrestin 2 effects are mediated. More importantly, we demonstrate that the induction of PC12 growth inhibition by Nerve Growth Factor is indeed dependent upon RAR b2 transcriptional activation in a b-arrestin 2-and ERK2-dependent manner.

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