Discovery of 6-(2,4-Dichlorophenyl)-5-[4-[(3
Animals
Breast Neoplasms
/ drug therapy
Crystallography, X-Ray
Dogs
Drug Discovery
/ methods
Drug Resistance, Neoplasm
Female
Half-Life
High-Throughput Screening Assays
Humans
Ligands
Mice
Models, Molecular
Pyrrolidines
/ chemical synthesis
Rats
Receptors, Estrogen
/ drug effects
Selective Estrogen Receptor Modulators
/ pharmacokinetics
Structure-Activity Relationship
Xenograft Model Antitumor Assays
Journal
Journal of medicinal chemistry
ISSN: 1520-4804
Titre abrégé: J Med Chem
Pays: United States
ID NLM: 9716531
Informations de publication
Date de publication:
23 01 2020
23 01 2020
Historique:
pubmed:
14
11
2019
medline:
28
7
2020
entrez:
14
11
2019
Statut:
ppublish
Résumé
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
Identifiants
pubmed: 31721572
doi: 10.1021/acs.jmedchem.9b01293
doi:
Substances chimiques
Ligands
0
Pyrrolidines
0
Receptors, Estrogen
0
Selective Estrogen Receptor Modulators
0
Types de publication
News
Langues
eng
Sous-ensembles de citation
IM