title: Synthesis and characterization of 3-arylquinazolinone and 3-arylquinazolinethione derivatives as selective estrogen receptor beta modulators.
abstract: On the basis of the stucture of genistein, a new series of 3-arylquinazolines was prepared and tested for their estrogen receptor (ER) alpha and beta 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 [IC(50)(ERbeta) = 179 nM] and 38-fold higher functional potency in a transcription assay [EC(50)(ERbeta) = 76 nM] with ERbeta than with ERalpha, thus improving upon the selectivity of genistein. All of the analogues showed preferential binding affinity for ERbeta. Many are also more potent in activating transcription by ERbeta than by ERalpha. 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 ERbeta over ERalpha [IC(50)(ERbeta) = 47 nM] and 215-fold higher potency in the transcription assay [EC(50)(ERbeta) = 13 nM]. These ERbeta-selective compounds may represent valuable tools in understanding the differences in structure and biological function of ERbeta and ERalpha.
authors.affiliation: Department of Chemistry, Bristol-Myers Squibb Pharmaceutical Research Institute, P.O. Box 4000, Princeton, NJ 08543-4000, USA. timur.gungor@bms.com
authors.forename: Timur
authors.initials: T
authors.lastname: Güngör
authors.forename: Ying
authors.initials: Y
authors.lastname: Chen
authors.forename: Rajasree
authors.initials: R
authors.lastname: Golla
authors.forename: Zhengping
authors.initials: Z
authors.lastname: Ma
authors.forename: James R
authors.initials: JR
authors.lastname: Corte
authors.forename: John P
authors.initials: JP
authors.lastname: Northrop
authors.forename: Bin
authors.initials: B
authors.lastname: Bin
authors.forename: John K
authors.initials: JK
authors.lastname: Dickson
authors.forename: Terry
authors.initials: T
authors.lastname: Stouch
authors.forename: Rong
authors.initials: R
authors.lastname: Zhou
authors.forename: Susan E
authors.initials: SE
authors.lastname: Johnson
authors.forename: Ramakrishna
authors.initials: R
authors.lastname: Seethala
authors.forename: Jean H M
authors.initials: JH
authors.lastname: Feyen
mesh_terms: D001665:Binding Sites; D001667:Binding, Competitive; D020847:Estrogen Receptor Modulators / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D047628:Estrogen Receptor alpha / Q000819:agonists* / Q000737:chemistry; D047629:Estrogen Receptor beta / Q000819:agonists* / Q000737:chemistry; D015394:Molecular Structure; D011799:Quinazolines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D052999:Quinazolinones; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013871:Thiones / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology
chemical_list: C510299:5,7-dihydroxy-3-(4-hydroxyphenyl)-4(3H)-quinazolinone; D020847:Estrogen Receptor Modulators; D047628:Estrogen Receptor alpha; D047629:Estrogen Receptor beta; D011799:Quinazolines; D052999:Quinazolinones; D013871:Thiones