RESUMEN
Activation of the G-protein coupled receptor (GPCR) Takeda G-protein receptor 5 (TGR5), also known as G-protein bile acid receptor 1 (GPBAR1), has been shown to play a key role in pathways associated with diabetes, metabolic syndrome, and autoimmune disease. Nipecotamide 5 was identified as an attractive starting point after a high-throughput screen (HTS) for receptor agonists. A comprehensive hit-to-lead effort culminated in the discovery of 45h as a potent, selective, and bioavailable TGR5 agonist to test in preclinical metabolic disease models. In genetically obese mice (ob/ob), 45h was as effective as a dipeptidyl peptidase-4 (DPP-4) inhibitor at reducing peak glucose levels in an acute oral glucose tolerance test (OGTT), but this effect was lost upon chronic dosing.
Asunto(s)
Hipoglucemiantes/síntesis química , Piperazinas/síntesis química , Receptores Acoplados a Proteínas G/agonistas , Administración Oral , Animales , Disponibilidad Biológica , Descubrimiento de Drogas , Péptido 1 Similar al Glucagón/análisis , Humanos , Hipoglucemiantes/farmacocinética , Hipoglucemiantes/farmacología , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Obesos , Piperazinas/farmacología , Relación Estructura-ActividadRESUMEN
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.
Asunto(s)
Anabolizantes/farmacología , Oxazinas/farmacología , Próstata/efectos de los fármacos , Quinolonas/farmacología , Receptores Androgénicos , Administración Oral , Anabolizantes/síntesis química , Antagonistas de Receptores Androgénicos , Andrógenos , Animales , Masculino , Modelos Químicos , Orquiectomía , Tamaño de los Órganos/efectos de los fármacos , Oxazinas/síntesis química , Próstata/anatomía & histología , Quinolonas/síntesis química , Ratas , Ratas Sprague-Dawley , Relación Estructura-Actividad , Testosterona/farmacologíaRESUMEN
The androgen receptor is a ligand inducible transcription factor that is involved in a broad range of physiological functions. Here we describe the discovery of a new class of orally available selective androgen receptor modulators. The lead compound, 6-[(2R,5R)-2-methyl-5-((R)-2,2,2-trifluoro-1-hydroxyethyl)pyrrolidin-1-yl]-4-trifluoromethylquinolin-2(1H)-one (6a), showed excellent anabolic activity in muscle with reduced effect on the prostate in a rat model of hypogonadism. The compound also improved bone strength in a rat model of post-menopausal osteoporosis.
Asunto(s)
Anabolizantes/síntesis química , Antagonistas de Receptores Androgénicos , Andrógenos , Conservadores de la Densidad Ósea/síntesis química , Pirrolidinas/síntesis química , Quinolinas/síntesis química , Quinolonas/síntesis química , Administración Oral , Anabolizantes/farmacocinética , Anabolizantes/farmacología , Animales , Disponibilidad Biológica , Conservadores de la Densidad Ósea/farmacocinética , Conservadores de la Densidad Ósea/farmacología , Femenino , Humanos , Hipogonadismo/tratamiento farmacológico , Hipogonadismo/patología , Masculino , Músculo Esquelético/efectos de los fármacos , Músculo Esquelético/metabolismo , Tamaño de los Órganos/efectos de los fármacos , Osteoporosis Posmenopáusica/tratamiento farmacológico , Próstata/efectos de los fármacos , Pirrolidinas/farmacocinética , Pirrolidinas/farmacología , Quinolinas/farmacocinética , Quinolinas/farmacología , Quinolonas/farmacocinética , Quinolonas/farmacología , Ratas , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
A series of 5-benzylidene-1,2-dihydro-2,2,4-trimethyl-5H-1-aza-6-oxa-chrysenes was synthesized and profiled for their ability to act as selective glucocorticoid receptor modulators (SGRMs). The synthesis and structure-activity relationships for this series of compounds are presented.
