Design and synthesis of aryl diphenolic azoles as potent and selective estrogen receptor-beta ligands.

Article Details


Malamas MS, Manas ES, McDevitt RE, Gunawan I, Xu ZB, Collini MD, Miller CP, Dinh T, Henderson RA, Keith JC Jr, Harris HA

Design and synthesis of aryl diphenolic azoles as potent and selective estrogen receptor-beta ligands.

J Med Chem. 2004 Oct 7;47(21):5021-40.

PubMed ID
15456246 [ View in PubMed

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.

DrugBank Data that Cites this Article

Binding Properties
DrugTargetPropertyMeasurementpHTemperature (°C)
2-(4-HYDROXY-PHENYL)BENZOFURAN-5-OLEstrogen receptor betaIC 50 (nM)6N/AN/ADetails
2-(5-HYDROXY-NAPHTHALEN-1-YL)-1,3-BENZOOXAZOL-6-OLEstrogen receptor betaIC 50 (nM)5N/AN/ADetails
3-(6-HYDROXY-NAPHTHALEN-2-YL)-BENZO[D]ISOOXAZOL-6-OLEstrogen receptor betaIC 50 (nM)1.4N/AN/ADetails
4-(6-HYDROXY-BENZO[D]ISOXAZOL-3-YL)BENZENE-1,3-DIOLEstrogen receptor betaIC 50 (nM)3.5N/AN/ADetails
EstradiolEstrogen receptor alphaIC 50 (nM)3.2N/AN/ADetails
EstradiolEstrogen receptor betaIC 50 (nM)3.6N/AN/ADetails
GenisteinEstrogen receptor alphaIC 50 (nM)395N/AN/ADetails
GenisteinEstrogen receptor betaIC 50 (nM)10N/AN/ADetails
PrinaberelEstrogen receptor betaIC 50 (nM)5N/AN/ADetails