Synthesis and Characterization of 3-Arylquinazolinone and 3-Arylquinazolinethione Derivatives as Selective Estrogen Receptor Beta Modulators

• Published in: Journal of medicinal chemistry 2006-04, Vol.49 (8), p.2440-2455
• Main Authors: Güngör, Timur, Chen, Ying, Golla, Rajasree, Ma, Zhengping, Corte, James R., Northrop, John P., Bin, Dickson, John K., Stouch, Terry, Zhou, Rong, Johnson, Susan E., Seethala, Ramakrishna, Feyen, Jean H. M.
• Format: Article
• Language: English
• Subjects: Binding Sites; Binding, Competitive; Biological and medical sciences; Estrogen Receptor alpha - agonists; Estrogen Receptor alpha - chemistry; Estrogen Receptor beta - agonists; Estrogen Receptor beta - chemistry; Estrogen Receptor Modulators - chemical synthesis; Estrogen Receptor Modulators - chemistry; Estrogen Receptor Modulators - pharmacology; Hormones. Endocrine system; Medical sciences; Molecular Structure; Pharmacology. Drug treatments; Quinazolines - chemical synthesis; Quinazolines - chemistry; Quinazolines - pharmacology; Quinazolinones; Stereoisomerism; Structure-Activity Relationship; Thiones - chemical synthesis; Thiones - chemistry; Thiones - pharmacology
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm0509389

On the basis of the stucture of genistein, a new series of 3-arylquinazolines was prepared and tested for their estrogen receptor (ER) α and β affinities. 5,7-Dihydroxy-3-(4-hydroxyphenyl)-4(3H)-quinazolinone (1aa) acts as an agonist on both ER subtypes. It has 62-fold higher binding affinity [IC50(ERβ) = 179 nM] and 38-fold higher functional potency in a transcription assay [EC50(ERβ) = 76 nM] with ERβ than with ERα, thus improving upon the selectivity of genistein. All of the analogues showed preferential binding affinity for ERβ. Many are also more potent in activating transcription by ERβ than by ERα. Transformation of the CO functionality at position 4 into a CS group provided 5,7-dihydroxy-3-(4-hydroxyphenyl)-4(3H)-quinazolinethione (1ba), which acts as an agonist on both ER subtypes but has 56-fold higher binding affinity for ERβ over ERα [IC50(ERβ) = 47 nM] and 215-fold higher potency in the transcription assay [EC50(ERβ) = 13 nM]. These ERβ-selective compounds may represent valuable tools in understanding the differences in structure and biological function of ERβ and ERα.