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Endocrinology Vol. 144, No. 10 4241-4249
Copyright © 2003 by The Endocrine Society

Evaluation of an Estrogen Receptor-ß Agonist in Animal Models of Human Disease

Heather A. Harris, Leo M. Albert, Yelena Leathurby, Michael S. Malamas, Richard E. Mewshaw, Chris P. Miller, Yogendra P. Kharode, James Marzolf, Barry S. Komm, Richard C. Winneker, Donald E. Frail, Ruth A. Henderson, Yuan Zhu and James C. Keith, Jr.

Women’s Health Research Institute (H.A.H., Y.P.K., J.M., B.S.K., R.C.W., D.E.F., R.A.H., Y.Z.) and Chemistry and Screening Sciences (R.E.M., C.P.M.), Wyeth Research, Collegeville, Pennsylvania 19426; Cardiovascular and Metabolic Diseases, Wyeth Research (L.M.A., Y.L., J.C.K.), Cambridge, Massachusetts 02140; and Chemistry and Screening Sciences, Wyeth Research (M.S.M.), Monmouth Junction, New Jersey 08852

Address all correspondence and requests for reprints to: Heather A. Harris, Ph.D., Women’s Health Research Institute, RN 3256, 500 Arcola Road, Collegeville, Pennsylvania 19426. E-mail: harrish{at}wyeth.com.

The discovery of a second estrogen receptor (ER), called ERß, in 1996 sparked intense interest within the scientific community to discover its role in mediating estrogen action. However, despite more than 6 yr of research into the function of this receptor, its physiological role in mediating estrogen action remains unclear and controversial. We have developed a series of highly selective agonists for ERß and have characterized their activity in several clinically relevant rodent models of human disease. The activity of one such compound, ERB-041, is reported here. We conclude from these studies that ERß does not mediate the bone-sparing activity of estrogen on the rat skeleton and that it does not affect ovulation or ovariectomy-induced weight gain. In addition, these compounds are nonuterotrophic and nonmammotrophic. However, ERB-041 has a dramatic beneficial effect in the HLA-B27 transgenic rat model of inflammatory bowel disease and the Lewis rat adjuvant-induced arthritis model. Daily oral doses as low as 1 mg/kg reverse the chronic diarrhea of HLA-B27 transgenic rats and dramatically improve histological disease scores in the colon. The same dosing regimen in the therapeutic adjuvant-induced arthritis model reduces joint scores from 12 (maximal inflammation) to 1 over a period of 10 d. Synovitis and Mankin (articular cartilage) histological scores are also significantly lowered (50–75%). These data suggest that one function of ERß may be to modulate the immune response, and that ERß-selective ligands may be therapeutically useful agents to treat chronic intestinal and joint inflammation.




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