RESUMO
Modification on a lead series of [1,4]oxazino[3,2-g]quinolin-7-ones at the 2-position led to selective androgen receptor modulators with improved in vivo activity. The most potent analog (-)-33a exhibited full maintenance of levator ani muscle at 3mg/kg and reduced activity on ventral prostate weight in a 2-week orally-dosed and orchidectomized rat maintenance assay.
Assuntos
Anabolizantes/farmacologia , Oxazinas/farmacologia , Próstata/efeitos dos fármacos , Quinolonas/farmacologia , Receptores Androgênicos , Administração Oral , Anabolizantes/síntese química , Antagonistas de Receptores de Andrógenos , Androgênios , Animais , Masculino , Modelos Químicos , Orquiectomia , Tamanho do Órgão/efeitos dos fármacos , Oxazinas/síntese química , Próstata/anatomia & histologia , Quinolonas/síntese química , Ratos , Ratos Sprague-Dawley , Relação Estrutura-Atividade , Testosterona/farmacologiaRESUMO
A series of androgen receptor modulators based on 8H-[1,4]oxazino[2,3-f]quinolin-8-ones was synthesized and evaluated in an androgen receptor transcriptional activation assay. The most potent analogues from the series exhibited single-digit nanomolar potency in vitro. Compound 18h demonstrated full efficacy in the maintenance of muscle weight, at 10 mg/kg, with reduced activity in prostate weight in an in vivo model of androgen action.
