Preclinical Characterization of Selective Estrogen Receptor β Agonists: New Insights into Their Therapeutic Potential
It has now been over 10 years since Jan-Ake Gustafsson revealed the existence of a second form of the estrogen receptor (ERβ) at a 1996 Keystone Symposium. Since then, substantial success has been made in distinguishing its potential biological functions from the previously known form (now called ERα) and how it might be exploited as a drug target. Subtype selective agonists have been particularly useful in this regard and suggest that ERβ agonists may be useful for a variety of clinical applications without triggering classic estrogenic side effects such as uterine stimulation. These applications include inflammatory bowel disease, rheumatoid arthritis, endometriosis, and sepsis. This manuscript will summarize illustrative data for three ERβ selective agonists, ERB-041, WAY-202196, and WAY-200070.
KeywordsSelective Agonist Colonic Epithelium Estradiol Benzoate Intestinal Barrier Epithelial Function Repeat Immobilization Stress
Our accomplishments in the field of ERβ research were enabled by the cooperative efforts of a number of scientists. First and foremost, Chris Miller, Mike Malamas, Rick Mewshaw, and Eric Manas led the chemistry effort to design and deliver highly selective ERβ agonists for biological characterization. Among the biologists, Jim Keith made key discoveries of in vivo activity; C. Richard Lyttle supported the team and suggested the endometriosis model evaluation. Several external collaborators have also contributed their expertise: Kaylon Bruner-Tran and Kevin Osteen (Vanderbilt University; endometriosis model), Kim Barrett and Silvia Resta-Lenert (University of California, San Diego; MDR1aKO mouse), Esther Sabban and Lydia Serova (New York Medical College, immobilization stress model), Steve Opal (Brown University; sepsis models). Finally I thank Rick Winneker for valuable suggestions on this manuscript.
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