Synthesis and structure-activity relationships of 1-benzylindane derivatives as selective agonists for estrogen receptor beta

The estrogen receptor beta (ER beta) selective agonist is considered a promising candidate for the treatment of estrogen deficiency symptoms in ER beta-expressing tissues, without the risk of breast cancer, and multiple classes of compounds have been reported as ER beta selective agonists. Among them, 6-6 bicyclic ring-containing structures (e.g., isoflavone phytoestrogens) are regarded as one of the cyclized analogues of isobutestrol 5b, and suggest that other cyclized scaffolds comprising 5-6 bicyclic rings could also act as selective ER beta ligands. In this study, we evaluated the selective ER beta agonistic activity of 1-(4-hydroxybenzyl)indan-5-ol 7a and studied structure-activity relationship (SAR) of its derivatives. Some functional groups improved the properties of 7a; introduction of a nitrile group on the indane-1-position resulted in higher selectivity for ER beta (12a), and further substitution with a fluoro or a methyl group to the pendant phenyl ring was also preferable (12b, d, and e). Subsequent chiral resolution of 12a identified that R-12a has a superior profile over S-12a. This is comparable to diarylpropionitrile (DPN) 5c, one of the promising selective ER beta agonists and indicates that this indane-based scaffold has the potential to provide better ER beta agonistic probes. (C) 2016 Elsevier Ltd. All rights reserved.