RESUMO
A series of 5,5-dimethylthiohydantoin derivatives were synthesized and evaluated for androgen receptor pure antagonistic activities for the treatment of hormone refractory prostate cancer. CH4933468 (32d) with a sulfonamide side chain not only exhibited antagonistic activity with no agonistic activity in the reporter gene assay but also inhibited the growth of bicalutamide-resistant cell lines. This compound also inhibited tumor growth of the LNCaP xenograft in mice dose-dependently.
Assuntos
Antagonistas de Androgênios , Antineoplásicos Hormonais , Ácidos Carboxílicos , Nitrilas/síntese química , Sulfonamidas/síntese química , Antagonistas de Androgênios/síntese química , Antagonistas de Androgênios/química , Antagonistas de Androgênios/farmacologia , Animais , Antineoplásicos Hormonais/síntese química , Antineoplásicos Hormonais/química , Antineoplásicos Hormonais/farmacologia , Ácidos Carboxílicos/síntese química , Ácidos Carboxílicos/química , Ácidos Carboxílicos/farmacologia , Linhagem Celular Tumoral , Relação Dose-Resposta a Droga , Concentração Inibidora 50 , Masculino , Camundongos , Camundongos SCID , Estrutura Molecular , Nitrilas/química , Nitrilas/uso terapêutico , Neoplasias da Próstata/tratamento farmacológico , Sulfonamidas/química , Sulfonamidas/uso terapêutico , Tioidantoínas/síntese química , Tioidantoínas/química , Tioidantoínas/farmacologia , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
The 3-(4-cyano-3-trifluoromethylphenyl)-5,5-dimethylthiohydantoin derivatives which have carboxy-terminal side chains were synthesized and their agonistic/antagonistic activities against androgen receptor (AR) measured. Among them, compound 13b showed antagonistic activity (IC50=130 nM) with no agonistic activity even at 10000 nM. This compound exhibited significant metabolic stability and oral antiandrogenic activity (ED50=7 mg/kg).
Assuntos
Antagonistas de Androgênios/síntese química , Antagonistas de Androgênios/farmacologia , Antagonistas de Receptores de Andrógenos , Animais , Ligação Competitiva/efeitos dos fármacos , Células CHO , Cricetinae , Cricetulus , Cristalografia por Raios X , Genes Reporter/efeitos dos fármacos , Células HeLa , Humanos , Indicadores e Reagentes , Masculino , Camundongos , Camundongos Endogâmicos ICR , Microssomos Hepáticos/efeitos dos fármacos , Microssomos Hepáticos/metabolismo , Modelos Moleculares , Glândulas Seminais/efeitos dos fármacos , Relação Estrutura-Atividade , Tioidantoínas/síntese química , Tioidantoínas/farmacologiaRESUMO
Lead optimization of CH4892280 (4), an androgen receptor (AR) pure antagonist, was investigated. Compounds 6 and 7, which have a carboxylic acid at the end of the side chain at the position 7alpha of dihydrotestosterone (DHT), showed partial agonistic activities in reporter gene assay (RGA). Conversion of the steroidal core structure to 17alpha-methyltestosterone gave compound 14, which showed weak pure antagonistic activity. Optimization of the side chain by the insertion of a phenyl ring led to compounds 22 and 28-30, which showed pure antagonistic activities at submicromolar concentrations. The structure-activity relationships were clarified.
Assuntos
Antagonistas de Receptores de Andrógenos , Receptores Androgênicos/metabolismo , Esteroides/química , Esteroides/farmacologia , Animais , Camundongos , Modelos Moleculares , Estrutura Molecular , Ligação Proteica , Receptores Androgênicos/química , Esteroides/síntese química , Relação Estrutura-AtividadeRESUMO
A series of 7alpha-substituted dihydrotestosterone derivatives were synthesized and evaluated for androgen receptor (AR) pure antagonistic activity. From reporter gene assay (RGA), the compound with a side chain containing N-n-butyl-N-methyl amide (19a) showed pure antagonistic activity (IC(50)=340nM, FI(5)>10,000nM), whereas known AR antagonists showed partial agonistic activities. The optimization of 19a led to compound 23 (CH4892280), which showed more potent pure antagonistic activity (IC(50)=190nM, FI(5)>10,000nM). The SARs of tested compounds suggested that the length of the side chain and the substituents on the amide nitrogen are important for pure antagonistic activities.