RESUMO
A novel, highly potent, orally active, nonsteroidal tissue selective androgen receptor (AR) modulator (BMS-564929) has been identified, and this compound has been advanced to clinical trials for the treatment of age-related functional decline. BMS-564929 is a subnanomolar AR agonist in vitro, is highly selective for the AR vs. other steroid hormone receptors, and exhibits no significant interactions with SHBG or aromatase. Dose response studies in castrated male rats show that BMS-564929 is substantially more potent than testosterone (T) in stimulating the growth of the levator ani muscle, and unlike T, highly selective for muscle vs. prostate. Key differences in the binding interactions of BMS-564929 with the AR relative to the native hormones were revealed through x-ray crystallography, including several unique contacts located in specific helices of the ligand binding domain important for coregulatory protein recruitment. Results from additional pharmacological studies effectively exclude alternative mechanistic contributions to the observed tissue selectivity of this unique, orally active androgen. Because concerns regarding the potential hyperstimulatory effects on prostate and an inconvenient route of administration are major drawbacks that limit the clinical use of T, the potent oral activity and tissue selectivity exhibited by BMS-564929 are expected to yield a clinical profile that provides the demonstrated beneficial effects of T in muscle and other tissues with a more favorable safety window.
Assuntos
Imidazóis/síntese química , Imidazóis/farmacologia , Músculo Esquelético/efeitos dos fármacos , Próstata/efeitos dos fármacos , Pirróis/síntese química , Pirróis/farmacologia , Receptores Androgênicos/metabolismo , Testosterona/análogos & derivados , Envelhecimento/metabolismo , Animais , Aromatase/metabolismo , Ligação Competitiva , Divisão Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Cristalografia por Raios X , Di-Hidrotestosterona/química , Di-Hidrotestosterona/metabolismo , Células Epiteliais/citologia , Células Epiteliais/efeitos dos fármacos , Humanos , Imidazóis/metabolismo , Ligantes , Hormônio Luteinizante/sangue , Masculino , Músculo Esquelético/fisiologia , Orquiectomia , Próstata/fisiologia , Estrutura Terciária de Proteína , Pirróis/metabolismo , Ratos , Ratos Sprague-Dawley , Receptores Androgênicos/química , Receptores Androgênicos/genética , Testosterona/química , Testosterona/metabolismo , Transcrição Gênica/fisiologiaRESUMO
Replacement of the 3-oxo group of 2-chloro-4-[(7R,7aS)-7-hydroxy-1,3-dioxotetrahydro-1H-pyrrolo[1,2c]imidazol-2(3H)-yl]-3-methylbenzonitrile resulted in a sulfamide series of selective androgen receptor modulator (SARM) agonists.
Assuntos
Androgênios , Congêneres da Testosterona/síntese química , Congêneres da Testosterona/farmacologia , Tiadiazóis/síntese química , Tiadiazóis/farmacologia , Animais , Relação Dose-Resposta a Droga , Masculino , Estrutura Molecular , Músculo Esquelético/efeitos dos fármacos , Músculo Esquelético/crescimento & desenvolvimento , Próstata/efeitos dos fármacos , Próstata/crescimento & desenvolvimento , Ligação Proteica , Ratos , Receptores Androgênicos/metabolismo , Relação Estrutura-AtividadeRESUMO
Pharmacokinetic studies in cynomolgus monkeys with a novel prototype selective androgen receptor modulator revealed trace amounts of an aniline fragment released through hydrolytic metabolism. This aniline fragment was determined to be mutagenic in an Ames assay. Subsequent concurrent optimization for target activity and avoidance of mutagenicity led to the identification of a pharmacologically superior clinical candidate without mutagenic potential.