Antagonists selective for estrogen receptor α

To develop compounds that are antagonists on ERalpha, but not ERbeta, we have added basic side-chains typically found in nonsteroidal antiestrogens to pyrazole compounds that bind with much higher affinity to ERalpha than to ERbeta. In this way we have developed basic side-chain pyrazoles (BSC-pyrazoles) that are high affinity, potent, selective antagonists on ERalpha. These BSC-pyrazoles are themselves inactive on ERalpha and ERbeta, and they antagonize E2 stimulation by ERalpha only. We investigated seven basic side-chain substituents on various alkyl-triaryl-substituted pyrazoles, and the most ERalpha-selective compound was methyl-piperidino-pyrazole (MPP). ERalpha-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 (TGFbeta3). In contrast to these BSC-pyrazoles, the antiestrogens trans-hydroxytamoxifen, raloxifene, and ICI 182,780 suppress E2 activity via both ERalpha and ERbeta. 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 ERalpha. These compounds should be useful in studying the biological functions of ERalpha and ERbeta and in selectively blocking responses that are mediated through ERalpha.