Abstract
A series of 5,5-dimethylthiohydantoin derivatives were synthesized and evaluated for androgen receptor pure antagonistic activities for the treatment of castration-resistant prostate cancer. Since CH4933468, which we reported previously, had a problem with agonist metabolites, novel thiohydantoin derivatives were identified by applying two strategies. One was the replacement of the alkylsulfonamide moiety by a phenylsulfonamide to avoid the production of agonist metabolites. The other was the replacement of the phenyl ring with a pyridine ring to improve in vivo potency and reduce hERG affinity. Pharmacological assays indicated that CH5137291 (17b) was a potent AR pure antagonist which did not produce the agonist metabolite. Moreover, CH5137291 completely inhibited in vivo tumor growth of LNCaP-BC2, a castration-resistant prostate cancer model.
Copyright © 2010 Elsevier Ltd. All rights reserved.
MeSH terms
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Androgen Antagonists / chemical synthesis*
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Androgen Antagonists / chemistry
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Androgen Antagonists / therapeutic use
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Animals
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Antineoplastic Agents / chemical synthesis*
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Antineoplastic Agents / chemistry
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Antineoplastic Agents / therapeutic use
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Castration
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Dogs
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Drug Design
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Ether-A-Go-Go Potassium Channels / metabolism
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Haplorhini
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Humans
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Male
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Mice
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Mice, Nude
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Microsomes, Liver / metabolism
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Phenytoin / analogs & derivatives
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Phenytoin / chemical synthesis
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Phenytoin / chemistry
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Phenytoin / therapeutic use
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Prostatic Neoplasms / drug therapy*
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Prostatic Neoplasms / surgery
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Rats
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Receptors, Androgen / chemistry*
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Receptors, Androgen / metabolism
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Structure-Activity Relationship
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Sulfonamides / chemical synthesis*
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Sulfonamides / chemistry
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Sulfonamides / therapeutic use
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Thiohydantoins / chemical synthesis*
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Thiohydantoins / chemistry
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Thiohydantoins / therapeutic use
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Transplantation, Heterologous
Substances
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6-(3-(4-cyano-3-trifluoromethylphenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)pyridine-2-sulfonic acid amide
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Androgen Antagonists
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Antineoplastic Agents
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Ether-A-Go-Go Potassium Channels
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Receptors, Androgen
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Sulfonamides
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Thiohydantoins
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diphenylthiohydantoin
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Phenytoin