erb-041 and Bone-Diseases--Metabolic

New diphenolic azoles as highly selective estrogen receptor-beta agonists are reported. The more potent and selective analogues of these series have comparable binding affinities for ERbeta as the natural ligand 17beta-estradiol but are >100-fold selective over ERalpha. Our design strategy not only followed a traditional SAR approach but also was supported by X-ray structures of ERbeta cocrystallized with various ligands as well as molecular modeling studies. These strategies enabled us to take advantage of a single conservative residue substitution in the ligand-binding pocket, ERalpha Met(421) --> ERbeta Ile(373), to optimize ERbeta selectivity. The 7-position-substituted benzoxazoles (Table 5) were the most selective ligands of both azole series, with ERB-041 (117) being >200-fold selective for ERbeta. The majority of ERbeta selective agonists tested that were at least approximately 50-fold selective displayed a consistent in vivo profile: they were inactive in several models of classic estrogen action (uterotrophic, osteopenia, and vasomotor instability models) and yet were active in the HLA-B27 transgenic rat model of inflammatory bowel disease. These data suggest that ERbeta-selective agonists are devoid of classic estrogenic effects and may offer a novel therapy to treat certain inflammatory conditions.

Topics: Androgen Antagonists; Animals; Animals, Genetically Modified; Anti-Inflammatory Agents, Non-Steroidal; Binding Sites; Body Temperature; Bone Diseases, Metabolic; Cell Line, Tumor; Crystallography, X-Ray; Drug Design; Estrogen Receptor beta; Female; HLA-B27 Antigen; Humans; Isoxazoles; Male; Mice; Models, Molecular; Organ Size; Phenols; Prostate; Radioligand Assay; Rats; Rats, Sprague-Dawley; Receptors, Estrogen; Structure-Activity Relationship; Transcription, Genetic; Uterus

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.

Topics: Animals; Animals, Genetically Modified; Arthritis, Experimental; beta 2-Microglobulin; Bone Density; Bone Diseases, Metabolic; Cell Line; Disease Models, Animal; Estrogen Receptor beta; Female; HLA-B27 Antigen; Humans; Inflammatory Bowel Diseases; Mammary Glands, Animal; Mice; Ovariectomy; Oxazoles; Rats; Rats, Inbred Lew; Rats, Sprague-Dawley; Receptors, Estrogen; Uterus; Weight Gain