785778-94-1Relevant articles and documents
Design and synthesis of aryl diphenolic azoles as potent and selective estrogen receptor-β ligands
Malamas, Michael S.,Manas, Eric S.,McDevitt, Robert E.,Gunawan, Iwan,Xu, Zhang B.,Collini, Michael D.,Miller, Chris P.,Dinh, Tam,Henderson, Ruth A.,Keith Jr., James C.,Harris, Heather A.
, p. 5021 - 5040 (2007/10/03)
New diphenolic azoles as highly selective estrogen receptor-β agonists are reported. The more potent and selective analogues of these series have comparable binding affinities for ERβ as the natural ligand 17β-estradiol but are > 100-fold selective over ERα. Our design strategy not only followed a traditional SAR approach but also was supported by X-ray structures of ERβ 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, ERα Met421 → ERβ Ile373, to optimize ERβ 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 ERβ. The majority of ERβ selective agonists tested that were at least sim;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 ERβ-selective agonists are devoid of classic estrogenic effects and may offer a novel therapy to treat certain inflammatory conditions.
