Antagonists Selective for Estrogen Receptor α.

To develop compounds that are antagonists on ER , but not ER , we have added basic side-chains typically found in nonsteroidal antiestrogens to pyrazole compounds that bind with much higher affinity to ER than to ER . In this way we have developed basic side-chain pyrazoles (BSC-pyrazoles) that are high affinity, potent, selective antagonists on ER . These BSCpyrazoles are themselves inactive on ER and ER , and they antagonize E2 stimulation by ER only. We investigated seven basic side-chain substituents on various alkyl-triaryl-substituted pyrazoles, and the most ER -selective compound was methyl-piperidino-pyrazole (MPP). ER -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 3). In contrast to these BSC-pyrazoles, the antiestrogens trans-hydroxytamoxifen, raloxifene, and ICI 182,780 suppress E2 activity via both ER and ER . 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 . These compounds should be useful in studying the biological functions of ER and ER and in selectively blocking responses that are mediated through ER . (Endocrinology 143: 941–947, 2002)