Journal
JOURNAL OF MEDICINAL CHEMISTRY
Volume 58, Issue 20, Pages 8128-8140Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acs.jmedchem.5b00984
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The discovery of an orally bioavailable selective estrogen receptor downregulator (SEED) with equivalent. potency and preclinical pharmacology to the intramuscular SEED fulvestrant is described. A directed screen identified the 1-aryl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole motif as a novel, druglike ER ligand. Aided by crystal structures of novel ligands bound to an ER construct, medicinal chemistry iterations led to (E)-343,5-difluoro-44(1R,3R)-2-(2-fluoro-2-methylpropyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido [3,4-b]-indol-1-yl)phenyl) acrylic acid (30b, AZD9496), a clinical candidate with high oral bioavailability across preclinical species that is currently being evaluated in phase I clinical trials for the treatment of advanced estrogen receptor (ER) positive breast cancer.
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