Estrogen receptor-β potency-selective ligands:: Structure-activity relationship studies of diarylpropionitriles and their acetylene and polar analogues

Through an effort to develop novel ligands that have subtype selectivity for the estrogen receptors alpha (ER alpha) and beta (ER beta), we have found that 2,3-bis(4-hydroxyphenyl)propionitrile (DPN) acts as an agonist on both ER subtypes, but has a 70-fold higher relative binding affinity and 170-fold higher relative potency in transcription assays with ER beta than with ER alpha. To investigate the ER beta affinity- and potency-selective character of this DPN further, we prepared a series of DPN analogues in which both the ligand core and the aromatic rings were modified by the repositioning of phenolic hydroxy groups and by the addition of alkyl substituents and nitrile groups. We also prepared other series of DPN analogues in which the nitrile functionality was replaced with acetylene groups or polar functions, to mimic the linear geometry or polarity of the nitrile, respectively. To varying degrees, all of the analogues show preferential binding affinity for ER beta (i.e., they are ER beta affinity-selective), and many, but not all of them, are also more potent in activating transcription through ER beta than through ER alpha (i.e., they are ER beta potency-selective). meso-2,3-Bis(4-hydroxyphenyl)succinonitrile and dl-2,3-bis(4-hydroxyphenyl)succinonitrile are among the, highest ER beta affinity-selective ligands, and they have an ER beta potency selectivity that is equivalent to that of DPN. The acetylene analogues have higher binding affinities but somewhat lower selectivities than their nitrile counterparts. The polar analogues have lower affinities, and only the fluorinated polar analogues have substantial affinity selectivities. This study suggests that, in this series of ligands, the nitrile functionality is critical to ER beta selectivity because it provides the optimal combination of linear geometry and polarity. Furthermore, the addition of a second nitrile group beta to the nitrile in DPN or the addition of a methyl substitutent at an ortho position on the beta -aromatic ring increases the affinity and selectivity of these compounds for ER beta. These ER beta -selective compounds may prove to be valuable tools in understanding the differences in structure and biological function of ER alpha and ER beta.