RESUMO
Oxobenzimidazoles (e.g., 1), a novel series of androgen receptor (AR) antagonists, were discovered through de novo design guided by structure-based drug design. The compounds in this series were reasonably permeable and metabolically stable, but suffered from poor solubility. The incorporation of three dimensional structural features led to improved solubility. In addition, the observation of a 'flipped' binding mode of an oxobenzimidazole analog in an AR ligand binding domain (LBD) model, led to the design and discovery of the novel oxindole series (e.g., 2) that is a potent full antagonist of AR.
Assuntos
Antagonistas de Receptores de Andrógenos/síntese química , Antineoplásicos/síntese química , Benzimidazóis/síntese química , Indóis/síntese química , Receptores Androgênicos/química , Antagonistas de Receptores de Andrógenos/farmacologia , Antineoplásicos/farmacologia , Benzimidazóis/farmacologia , Linhagem Celular Tumoral , Desenho de Fármacos , Descoberta de Drogas , Humanos , Indóis/farmacologia , Ligantes , Masculino , Modelos Moleculares , Neoplasias da Próstata , Ligação Proteica , Estrutura Secundária de Proteína , Estrutura Terciária de Proteína , Receptores Androgênicos/metabolismo , Solubilidade , Relação Estrutura-AtividadeRESUMO
High throughput cell-based screening led to the identification of 3-aryloxy lactams as potent androgen receptor (AR) antagonists. Refinement of these leads to improve the ADME profile and remove residual agonism led to the discovery of 12, a potent full antagonist with greater oral bioavailability. Improvements in the ADME profile were realized by designing more ligand-efficient molecules with reduced molecular weights and lower lipophilicities.
Assuntos
Descoberta de Drogas , Lactamas/farmacologia , Neoplasias da Próstata/tratamento farmacológico , Receptores Androgênicos/química , Relação Dose-Resposta a Droga , Ensaios de Triagem em Larga Escala , Humanos , Lactamas/síntese química , Lactamas/química , Masculino , Modelos Moleculares , Estrutura Molecular , Neoplasias da Próstata/cirurgia , Receptores Androgênicos/metabolismo , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
N-(Pyridin-2-yl) arylsulfonamides are identified as inhibitors of 11beta-hydroxysteroid dehydrogenase type 1 (11betaHSD1), an enzyme that catalyzes the reduction of the glucocorticoid cortisone to cortisol. Dysregulation of glucocorticoids has been implicated in the pathogenesis of diabetes and the metabolic syndrome. In this Letter, we present the development of an initial lead to an efficient ligand with improved physiochemical properties using a deletion strategy. This strategy allowed for further optimization of potency leading to the discovery of the clinical candidate PF-915275.
Assuntos
11-beta-Hidroxiesteroide Desidrogenase Tipo 1/antagonistas & inibidores , Aminopiridinas/síntese química , Inibidores Enzimáticos/síntese química , Sulfonamidas/síntese química , 11-beta-Hidroxiesteroide Desidrogenase Tipo 1/metabolismo , Aminopiridinas/química , Aminopiridinas/farmacocinética , Animais , Linhagem Celular , Simulação por Computador , Cricetinae , Cristalografia por Raios X , Desenho de Fármacos , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacocinética , Humanos , Ratos , Relação Estrutura-Atividade , Sulfonamidas/química , Sulfonamidas/farmacocinéticaRESUMO
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.