title: Antagonists selective for estrogen receptor alpha.
abstract: To develop compounds that are antagonists on ER(alpha), but not ER(beta), we have added basic side-chains typically found in nonsteroidal antiestrogens to pyrazole compounds that bind with much higher affinity to ER(alpha) than to ER(beta). In this way we have developed basic side-chain pyrazoles (BSC-pyrazoles) that are high affinity, potent, selective antagonists on ER(alpha). These BSC-pyrazoles are themselves inactive on ER(alpha) and ER(beta), and they antagonize E2 stimulation by ER(alpha) only. We investigated seven basic side-chain substituents on various alkyl-triaryl-substituted pyrazoles, and the most ER(alpha)-selective compound was methyl-piperidino-pyrazole (MPP). ER(alpha)-selective antagonism was observed on diverse reporter-promoter gene constructs containing estrogen response elements that are consensus, nonconsensus (pS2), or comprised of multiple half-estrogen response elements (NHERF/EBP50) and on genes in which ER works indirectly by tethering to other DNA-bound proteins (TGF(beta)3). In contrast to these BSC-pyrazoles, the antiestrogens trans-hydroxytamoxifen, raloxifene, and ICI 182,780 suppress E2 activity via both ER(alpha) and ER(beta). The most effective BSC-pyrazole, MPP, fully antagonized E2 stimulation of pS2 mRNA in MCF-7 breast cancer cells, consistent with the fact that these cells contain almost exclusively ER(alpha). These compounds should be useful in studying the biological functions of ER(alpha) and ER(beta) and in selectively blocking responses that are mediated through ER(alpha).
authors.affiliation: Department of Molecular and Integrative Physiology, University of Illinois and University of Illinois College of Medicine, Urbana, Illinois 61801, USA.
authors.forename: Jun
authors.initials: J
authors.lastname: Sun
authors.forename: Ying R
authors.initials: YR
authors.lastname: Huang
authors.forename: William R
authors.initials: WR
authors.lastname: Harrington
authors.forename: Shubin
authors.initials: S
authors.lastname: Sheng
authors.forename: John A
authors.initials: JA
authors.lastname: Katzenellenbogen
authors.forename: Benita S
authors.initials: BS
authors.lastname: Katzenellenbogen
mesh_terms: D004965:Estrogen Antagonists / Q000138:chemical synthesis / Q000494:pharmacology*; D047628:Estrogen Receptor alpha; D047629:Estrogen Receptor beta; D006801:Humans; D010957:Plasmids / Q000235:genetics; D011720:Pyrazoles / Q000138:chemical synthesis* / Q000494:pharmacology*; D011960:Receptors, Estrogen / Q000037:antagonists & inhibitors* / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D020845:Selective Estrogen Receptor Modulators / Q000138:chemical synthesis / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D014162:Transfection; D014407:Tumor Cells, Cultured
chemical_list: D004965:Estrogen Antagonists; D047628:Estrogen Receptor alpha; D047629:Estrogen Receptor beta; D011720:Pyrazoles; D011960:Receptors, Estrogen; D020845:Selective Estrogen Receptor Modulators