Discovery of 6-(2,4-Dichlorophenyl)-5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-8,9-dihydro-7H-benzo[7]annulene-2-carboxylic acid (SAR439859), a Potent and Selective Estrogen Receptor Degrader (SERD) for the Treatment of Estrogen Receptor Positive Breast Cancer.

More than 75 % of breast cancers are estrogen receptor alpha (ER) positive (ER+) and resistance to current hormone therapies occurs in one third of ER+ patients. Tumor resistance is still ERdependent, but mutations usually confer constitutive activation to the hormone-receptor, rendering ERmodulator drugs such as tamoxifen and aromatase inhibitors ineffective. Fulvestrant is a potent Selective Estrogen Receptor Degrader (SERD), which degrades the ERreceptor in drug-resistant tumors and has been approved for the treatment of hormone receptor positive metastatic breast cancer following antiestrogen therapy. However, fulvestrant shows poor pharmacokinetic properties in human, low solubility, weak permeation and high metabolism, limiting its administration to inconvenient intramuscular injections. This paper describes the identification and optimization of a new series of potent orally available SERDs, which led to the discovery of 6-(2,4-Dichlorophenyl)-5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-8,9-dihydro-7H-benzo[7]annulene-2-carboxylic acid (43d), showing promising antitumor activity in breast cancer mice xenograft models and whose properties warranted clinical evaluation.