Author: Carr, Miriam ; Egan, Billy ; Zisterer, Daniela M ; Meegan, Mary J ; Lloyd, David G ; O'Boyle, Niamh ; McCabe, Thomas ; Wang, Shu ; Knox, Andrew J S ; Twamley, Brendan ; Nevin, Daniel K

4-Aryl-4H-Chromene derivatives have been previously shown to exhibit anti-proliferative, apoptotic and anti-angiogenic activity in a variety of tumor models in vitro and in vivo generally via activation of caspases through inhibition of tubulin polymerisation. We have previously identified by Virtual Screening (VS) a 4-aryl-4H-chromene scaffold, of which two examples were shown to bind Estrogen Receptor α and β with low nanomolar affinity and <20-fold selectivity for α over β and low micromolar anti-proliferative activity in the MCF-7 cell line. Thus, using the 4-aryl-4H-chromene scaffold as a starting point, a series of compounds with a range of basic arylethers at C-4 and modifications at the C3-ester substituent of the benzopyran ring were synthesised, producing some potent ER antagonists in the MCF-7 cell line which were highly selective for ERα (compound 35; 350-fold selectivity) or ERβ (compound 42; 170-fold selectivity).

01 Feb 2014·Letters in Drug Design & Discovery

Prediction of the Estrogen Receptor Binding Affinity for both hER<sub>α</sub> and hER<sub>β</sub> by QSAR Approaches

Author: Luan, Feng ; Cordeiro, Maria Natalia Dias Soeiro ; Lu, Hongying ; Chen, Xuanxuan ; Yang, Xin ; Deng, Changliang

A QSAR study is reported to predict the binding affinity of a set of 81 modulators for both of human estrogen receptor α and β (ERα and ERβ).In this study, the derived QSAR models were built by forward stepwise multilinear regression (MLR) and nonlinear radial basis function neural networks (RBFNN), resp.The statistical characteristics of the external test set provided by multiple linear model (R2=0.814, F=61.277, RMS=0.5461 for ERα; R2=0.600, F=21.039, RMS=0.6707 for ERβ) indicated satisfactory stability and predictive ability of the model built.The predictive ability for ERβ of RBFNN model is somewhat superior: R2=0.7691, F=32.012, RMS=0.5764, and the similar result was obtained for ERα of the test set: R2=0.7950, F=54.131 RMS=0.3120.Overall, the appropriate results proved the models to be meaningful and useful to predict and virtual screen of the derivatives with high binding activity.

15 Apr 2010·The Journal of Infectious DiseasesQ2 · MEDICINE

Estrogen Receptor β Agonism Increases Survival in Experimentally Induced Sepsis and Ameliorates the Genomic Sepsis Signature: A Pharmacogenomic Study

Q2 · MEDICINE

Article

Author: Richard E. Mewshaw ; Michael S. Malamas ; Lisa Racie ; George P. Vlasuk ; John E. Palardy ; Heather A. Harris ; Steven M. Opal ; Edward Lavallie ; James C. Keith ; Eirini Christaki ; William Mounts ; Nubar Kessinian ; Nicolas A. Parejo

BACKGROUNDNonsteroidal agonists have been developed that selectively bind to and activate estrogen receptor beta (ERbeta) rather than estrogen receptor alpha (ERalpha). ERbeta is expressed equally in both male and female mammals in multiple extragonadal tissues. Work reported elsewhere has demonstrated that ERbeta agonists have beneficial effects in multiple (but not all) models of inflammatory diseases and also increase survival in experimentally induced sepsis.METHODSIn these experiments, ERbeta agonists (ERB-041 or WAY-202196) were compared with vehicle control in the murine cecal ligation and puncture (CLP) model and in the pneumococcal pneumonia model of sepsis. The effect of WAY-202196 on the gene expression profile in the CLP model was further studied by transcriptome analysis of lung and small intestine tissue samples.RESULTSERbeta agonists provided a significant survival benefit in both experimental models of bacterial sepsis. This survival advantage was accompanied by reduced histologic evidence of tissue damage, reduced transcription of multiple proinflammatory proteins by transcriptome analysis and was not associated with increased bacterial outgrowth.CONCLUSIONSERbeta agonist administration provided a survival advantage in septic animals and appears to be a promising therapeutic modality in sepsis.

100 Deals associated with ERB-196

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Indication	Highest Phase	Country/Location	Organization	Date
Inflammation	Phase 1	United States	Wyeth Ltd. (India)	-
Inflammation	Phase 1	-	Pfizer Inc.	-
Sepsis	Phase 1	United States	Wyeth Ltd. (India)	-

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