Optimization of
a Novel Binding Motif to (<i>E</i>)‑3-(3,5-Difluoro-4-((1<i>R</i>,3<i>R</i>)‑2-(2-fluoro-2-methylpropyl)-3-methyl-2,3,4,9-tetrahydro‑1<i>H</i>‑pyrido[3,4‑<i>b</i>]indol-1-yl)phenyl)acrylic
Acid (AZD9496), a Potent and Orally Bioavailable Selective Estrogen
Receptor Downregulator and Antagonist
- Publication date
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Abstract
The
discovery of an orally bioavailable selective estrogen receptor
downregulator (SERD) with equivalent potency and preclinical pharmacology
to the intramuscular SERD fulvestrant is described. A directed screen
identified the 1-aryl-2,3,4,9-tetrahydro-1<i>H</i>-pyrido[3,4-<i>b</i>]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 (<i>E</i>)-3-(3,5-difluoro-4-((1<i>R</i>,3<i>R</i>)-2-(2-fluoro-2-methylpropyl)-3-methyl-2,3,4,9-tetrahydro-1<i>H</i>-pyrido[3,4-<i>b</i>]indol-1-yl)phenyl)acrylic
acid (<b>30b</b>, 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