RESUMO
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.
Assuntos
Hipoglicemiantes/síntese química , Piperazinas/síntese química , Receptores Acoplados a Proteínas G/agonistas , Administração Oral , Animais , Disponibilidade Biológica , Descoberta de Drogas , Peptídeo 1 Semelhante ao Glucagon/análise , Humanos , Hipoglicemiantes/farmacocinética , Hipoglicemiantes/farmacologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Obesos , Piperazinas/farmacologia , Relação Estrutura-AtividadeRESUMO
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
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.
Assuntos
Anabolizantes/síntese química , Antagonistas de Receptores de Andrógenos , Androgênios , Conservadores da Densidade Óssea/síntese química , Pirrolidinas/síntese química , Quinolinas/síntese química , Quinolonas/síntese química , Administração Oral , Anabolizantes/farmacocinética , Anabolizantes/farmacologia , Animais , Disponibilidade Biológica , Conservadores da Densidade Óssea/farmacocinética , Conservadores da Densidade Óssea/farmacologia , Feminino , Humanos , Hipogonadismo/tratamento farmacológico , Hipogonadismo/patologia , Masculino , Músculo Esquelético/efeitos dos fármacos , Músculo Esquelético/metabolismo , Tamanho do Órgão/efeitos dos fármacos , Osteoporose Pós-Menopausa/tratamento farmacológico , Próstata/efeitos dos fármacos , Pirrolidinas/farmacocinética , Pirrolidinas/farmacologia , Quinolinas/farmacocinética , Quinolinas/farmacologia , Quinolonas/farmacocinética , Quinolonas/farmacologia , Ratos , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
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.