Antagonists selective for estrogen receptor α

To develop compounds that are antagonists on ERα, but not ERβ, we have added basic side-chains typically found in non-steroidal antiestrogens to pyrazole compounds that bind with much higher affinity to ERα than to ERβ. In this way we have developed basic side-chain pyrazoles (BSC-pyrazoles) that are high affinity, potent, selective antagonists on ERα. These BSC-pyrazoles are themselves inactive on ERα and ERβ, and they antagonize E2 stimulation by ERα only. We investigated seven basic side-chain substituents on various alkyl-triaryl-substituted pyrazoles, and the most ERα-selective compound was methyl-piperidino-pyrazole (MPP). ERα-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 (TGFβ3). In contrast to these BSC-pyrazoles, the antiestrogens trans-hydroxytamoxifen, raloxifene, and ICI 182,780 suppress E2 activity via both ERα and ERβ. 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 ERα. These compounds should be useful in studying the biological functions of ERα and ERβ and in selectively blocking responses that are mediated through ERα.