1. Discovery of 6-(2,4-Dichlorophenyl)-5-[4-[(3 S )-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-8,9-dihydro-7 H -benzo[7]annulene-2-carboxylic acid (SAR439859), a Potent and Selective Estrogen Receptor Degrader (SERD) for the Treatment of Estrogen-Receptor-Positive Breast Cancer.
- Author
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El-Ahmad Y, Tabart M, Halley F, Certal V, Thompson F, Filoche-Rommé B, Gruss-Leleu F, Muller C, Brollo M, Fabien L, Loyau V, Bertin L, Richepin P, Pilorge F, Desmazeau P, Girardet C, Beccari S, Louboutin A, Lebourg G, Le-Roux J, Terrier C, Vallée F, Steier V, Mathieu M, Rak A, Abecassis PY, Vicat P, Benard T, Bouaboula M, Sun F, Shomali M, Hebert A, Levit M, Cheng H, Courjaud A, Ginesty C, Perrault C, Garcia-Echeverria C, McCort G, and Schio L
- Subjects
- Animals, Breast Neoplasms metabolism, Crystallography, X-Ray, Dogs, Drug Resistance, Neoplasm, Female, Half-Life, High-Throughput Screening Assays, Humans, Ligands, Mice, Models, Molecular, Rats, Receptors, Estrogen drug effects, Selective Estrogen Receptor Modulators pharmacokinetics, Selective Estrogen Receptor Modulators pharmacology, Structure-Activity Relationship, Xenograft Model Antitumor Assays, Breast Neoplasms drug therapy, Drug Discovery methods, Pyrrolidines chemical synthesis, Pyrrolidines pharmacology, Receptors, Estrogen metabolism, Selective Estrogen Receptor Modulators therapeutic use
- Abstract
More than 75% of breast cancers are estrogen receptor alpha (ERα) positive (ER+), and resistance to current hormone therapies occurs in one-third of ER+ patients. Tumor resistance is still ERα-dependent, but mutations usually confer constitutive activation to the hormone receptor, rendering ERα modulator drugs such as tamoxifen and aromatase inhibitors ineffective. Fulvestrant is a potent selective estrogen receptor degrader (SERD), which degrades the ERα 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 Drug Annotation 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-[(3 S )-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-8,9-dihydro-7 H -benzo[7]annulene-2-carboxylic acid ( 43d ), showing promising antitumor activity in breast cancer mice xenograft models and whose properties warranted clinical evaluation.
- Published
- 2020
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