☆ 4.7 Article

Optimization of a Novel Binding Motif to (E)-3-(3,5-Difluoro-4-((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 (AZD9496), a Potent and Orally Bioavailable Selective Estrogen Receptor Downregulator and Antagonist

JOURNAL OF MEDICINAL CHEMISTRY (2015)

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JOURNAL OF MEDICINAL CHEMISTRY

卷 58, 期 20, 页码 8128-8140

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AMER CHEMICAL SOC

DOI: 10.1021/acs.jmedchem.5b00984

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Chemistry, Medicinal

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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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