1u3q
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Crystal Structure of Estrogen Receptor beta complexed with CL-272
OverviewOverview
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.
About this StructureAbout this Structure
1U3Q is a Single protein structure of sequence from Homo sapiens with 272 as ligand. Full crystallographic information is available from OCA.
ReferenceReference
Design and synthesis of aryl diphenolic azoles as potent and selective estrogen receptor-beta ligands., Malamas MS, Manas ES, McDevitt RE, Gunawan I, Xu ZB, Collini MD, Miller CP, Dinh T, Henderson RA, Keith JC Jr, Harris HA, J Med Chem. 2004 Oct 7;47(21):5021-40. PMID:15456246
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