Evaluation of an estrogen receptor-beta agonist in animal models of human disease.
The discovery of a second estrogen receptor (ER), called ERbeta, 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 ERbeta 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 ERbeta 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 ERbeta may be to modulate the immune response, and that ERbeta-selective ligands may be therapeutically useful agents to treat chronic intestinal and joint inflammation.
D000818:Animals; D030801:Animals, Genetically Modified; D001169:Arthritis, Experimental / Q000188:drug therapy; D015519:Bone Density / Q000187:drug effects; D001851:Bone Diseases, Metabolic / Q000188:drug therapy; D002460:Cell Line; D004195:Disease Models, Animal; D047629:Estrogen Receptor beta; D005260:Female; D015796:HLA-B27 Antigen / Q000276:immunology; D006801:Humans; D015212:Inflammatory Bowel Diseases / Q000188:drug therapy / Q000276:immunology; D008321:Mammary Glands, Animal / Q000187:drug effects; D051379:Mice; D010052:Ovariectomy; D010080:Oxazoles / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use; D051381:Rats; D011917:Rats, Inbred Lew; D017207:Rats, Sprague-Dawley; D011960:Receptors, Estrogen / Q000819:agonists* / Q000378:metabolism; D014599:Uterus / Q000187:drug effects; D015430:Weight Gain / Q000187:drug effects; D001613:beta 2-Microglobulin / Q000276:immunology
C478102:ERB 041; D047629:Estrogen Receptor beta; D015796:HLA-B27 Antigen; D010080:Oxazoles; D011960:Receptors, Estrogen; D001613:beta 2-Microglobulin