European Journal of Medicinal Chemistry 2011-06-01

Selective and potent agonists for estrogen receptor beta derived from molecular refinements of salicylaldoximes.

Simone Bertini, Andrea De Cupertinis, Carlotta Granchi, Barbara Bargagli, Tiziano Tuccinardi, Adriano Martinelli, Marco Macchia, Jillian R Gunther, Kathryn E Carlson, John A Katzenellenbogen, Filippo Minutolo

Index: Eur. J. Med. Chem. 46 , 2453-62, (2011)

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Abstract

In a continuing effort to improve the subtype selectivity and agonist potency of estrogen receptor β (ERβ) ligands, we have designed and developed a thus far unexplored structural series obtained by molecular refinements of monoaryl-substituted salicylaldoximes (Salaldox B). The most interesting compounds in this series (2c, d) show remarkably high ERβ-binding affinities, with Ki values reaching the sub-nanomolar range (Ki=0.38 nM for 2c and 0.57 nM for 2d), and have very high levels of ERβ-subtype selectivity. Both compounds show a potent full agonist character on ERβ (EC50=0.23 nM for 2c and 1.3 nM for 2d). Furthermore, 2d shows a remarkable functional subtype selectivity, with a β/α transcription potency ratio 50-fold higher than that of estradiol.Copyright © 2011 Elsevier Masson SAS. All rights reserved.