Journal
JOURNAL OF MEDICINAL CHEMISTRY
Volume 52, Issue 3, Pages 858-867Publisher
AMER CHEMICAL SOC
DOI: 10.1021/jm801458t
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Funding
- National Institutes of Health [R37DKI5556, R01 CA 18119, P41 RR01081]
- Italian Ministry for University and Research (MIUR)
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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 ER beta-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 ER beta over ER alpha. Moreover, in transcription assays, it proved to be a selective and potent ER beta-full agonist with an EC50 of 4.8 nM.
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