Abstract
An aryloxy tetramethylcyclobutane was identified as a novel template for androgen receptor (AR) antagonists via cell-based high-throughput screening. Follow-up to the initial "hit" established 5 as a viable lead. Further optimization to achieve full AR antagonism led to the discovery of 26 and 30, both of which demonstrated excellent in vivo tumor growth inhibition upon oral administration in a castration-resistant prostate cancer (CRPC) animal model.
MeSH terms
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Administration, Oral
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Androgen Antagonists / chemical synthesis*
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Androgen Antagonists / pharmacokinetics
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Androgen Antagonists / pharmacology
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Androgens / chemical synthesis
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Androgens / pharmacokinetics
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Androgens / pharmacology
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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 / pharmacology
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Bridged Bicyclo Compounds, Heterocyclic / chemical synthesis*
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Bridged Bicyclo Compounds, Heterocyclic / pharmacokinetics
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Bridged Bicyclo Compounds, Heterocyclic / pharmacology
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Cell Line
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Cyclobutanes / chemical synthesis*
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Cyclobutanes / pharmacokinetics
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Cyclobutanes / pharmacology
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Drug Resistance, Neoplasm
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High-Throughput Screening Assays
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Humans
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Ligands
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Male
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Mice
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Mice, Nude
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Models, Molecular
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Prostatic Neoplasms / drug therapy
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Prostatic Neoplasms / pathology
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Pyrazoles / chemical synthesis*
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Pyrazoles / pharmacokinetics
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Pyrazoles / pharmacology
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Structure-Activity Relationship
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Xenograft Model Antitumor Assays
Substances
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Androgen Antagonists
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Androgens
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Antineoplastic Agents
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Bridged Bicyclo Compounds, Heterocyclic
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Cyclobutanes
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Ligands
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N,N-(3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-1-(2-(methylamino)-2-oxoethyl)-1H-pyrazole-3-carboxamide
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N-(3-((5-cyano-6-methylpyridin-2-yl)oxy)-2,2,4,4-tetramethylcyclobutyl)imidazo(1,2-a)pyrimidine-3-carboxamide
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Pyrazoles