Synthesis of 11β-ether-17α-ethinyl-3,17β-estradiols with strong ER antagonist activities

Abstract We have previously found that several families of nonpolar short chain 11 β -ethers and esters of estradiol are selective estrogen receptor modulators (SERMs). Surprisingly, the transformation from potent estrogen to anti-estrogen occurs when the 11 β -side chain is increased slightly in length from four to five non-hydrogen atoms. To generate strong antagonists for preclinical development, we have synthesized other similar ER ligands with 11 β -ethers and with an additional ethinyl group at the 17 α -position in order to slow metabolism of the steroidal moiety. Here we report the synthesis and biological activity of two such compounds (11 β - i -PrO-propyl and 11 β - t -BuO-propyl ethers) with extremely strong antagonist activities.