Structural evolutions of salicylaldoximes as selective agonists for estrogen receptor beta.
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Minutolo F, Bertini S, Granchi C, Marchitiello T, Prota G, Rapposelli S, Tuccinardi T, Martinelli A, Gunther JR, Carlson KE, Katzenellenbogen JA, Macchia M
Structural evolutions of salicylaldoximes as selective agonists for estrogen receptor beta.
J Med Chem. 2009 Feb 12;52(3):858-67. doi: 10.1021/jm801458t.
- PubMed ID
- 19128016 [ View in PubMed]
- Abstract
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.
DrugBank Data that Cites this Article
- Binding Properties
Drug Target Property Measurement pH Temperature (°C) Estradiol Estrogen receptor alpha EC 50 (nM) 0.7 N/A N/A Details Estradiol Estrogen receptor beta EC 50 (nM) 0.13 N/A N/A Details