2009/01/07 by Filippo Minutolo, Simone Bertini, Carlotta Granchi +9 · 2 citations
Biochemistry, Genetics and Molecular Biology · Medicine · Computer Science · #Estrogen and related hormone effects #Inflammatory mediators and NSAID effects #Computational Drug Discovery Methods
paper · doi:10.1021/jm801458t
openalex publication_date 2009/01/07 · openalex created_date 2016/06/24 · openalex updated_date 2026/08/01
The bioisosteric replacement of the phenol ring, a signature functional group of most estrogen receptor (ER) ligands, with a hydrogen-bonded pseudocyclic ring, led to the development of a novel class of nonsteroidal ER-ligands based on a salicylaldoxime template. A series of structural modifications were applied to selected molecules belonging to the monoaryl-salicylaldoxime chemical class in an attempt to improve further their ERbeta-selective receptor affinity and agonist properties. Among several modifications, the best results were obtained by the simultaneous introduction of a meta-fluorine atom into the para-hydroxyphenyl substituent present in the 4-position of salicylaldoxime, together with the insertion of a chloro group in the 3-position of the central scaffold. The resulting compound showed the best affinity (K(i) = 7.1 nM) and selectivity for ERbeta over ERalpha. Moreover, in transcription assays, it proved to be a selective and potent ERbeta-full agonist with an EC(50) of 4.8 nM.