Abstract
Herein, we report the identification and synthesis of a series of tricyclic indazoles as a novel class of selective estrogen receptor degrader antagonists. Replacement of a phenol, present in our previously reported tetrahydroisoquinoline scaffold, with an indazole group led to the removal of a reactive metabolite signal in an in vitro glutathione trapping assay. Further optimization, guided by X-ray crystal structures and NMR conformational work, varied the alkyl side chain and pendant aryl group and resulted in compounds with low turnover in human hepatocytes and enhanced chemical stability. Compound 9 was profiled as a representative of the series in terms of pharmacology and demonstrated the desired estrogen receptor α degrader-antagonist profile and demonstrated activity in a xenograft model of breast cancer.
MeSH terms
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Animals
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Antineoplastic Agents / chemical synthesis
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Antineoplastic Agents / pharmacokinetics
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Antineoplastic Agents / therapeutic use*
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Breast Neoplasms / drug therapy*
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Dogs
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Drug Screening Assays, Antitumor
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Estrogen Receptor Antagonists / chemical synthesis
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Estrogen Receptor Antagonists / pharmacokinetics
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Estrogen Receptor Antagonists / therapeutic use*
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Estrogen Receptor alpha / metabolism
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Heterocyclic Compounds, 3-Ring / chemical synthesis
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Heterocyclic Compounds, 3-Ring / pharmacokinetics
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Heterocyclic Compounds, 3-Ring / therapeutic use*
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Humans
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Indazoles / chemical synthesis
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Indazoles / pharmacokinetics
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Indazoles / therapeutic use*
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MCF-7 Cells
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Male
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Mice, SCID
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Microsomes, Liver / metabolism
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Molecular Structure
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Rats
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Structure-Activity Relationship
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Xenograft Model Antitumor Assays
Substances
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Antineoplastic Agents
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Estrogen Receptor Antagonists
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Estrogen Receptor alpha
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Heterocyclic Compounds, 3-Ring
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Indazoles