way-200070 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