Synthesis and characterization of 3-arylquinazolinone and 3-arylquinazolinethione derivatives as selective estrogen receptor beta modulators.
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.
Güngör
Timur
T
Department of Chemistry, Bristol-Myers Squibb Pharmaceutical Research Institute, P.O. Box 4000, Princeton, NJ 08543-4000, USA. timur.gungor@bms.com
Chen
Ying
Y
Golla
Rajasree
R
Ma
Zhengping
Z
Corte
James R
JR
Northrop
John P
JP
Bin
Bin
B
Dickson
John K
JK
Stouch
Terry
T
Zhou
Rong
R
Johnson
Susan E
SE
Seethala
Ramakrishna
R
Feyen
Jean H M
JH
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
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