RESUMEN
Recent literature reports highlight the importance of the renal outer medullary potassium (ROMK) channel in renal sodium and potassium homeostasis and emphasize the potential impact that ROMK inhibitors could have as a novel mechanism diuretic in heart failure patients. A series of piperazine-based ROMK inhibitors were designed and optimized to achieve excellent ROMK potency, hERG selectivity, and ADME properties, which led to the identification of compound 28 (BMS-986308). BMS-986308 demonstrated efficacy in the volume-loaded rat diuresis model as well as promising in vitro and in vivo profiles and was therefore advanced to clinical development.
Asunto(s)
Insuficiencia Cardíaca , Bloqueadores de los Canales de Potasio , Animales , Insuficiencia Cardíaca/tratamiento farmacológico , Humanos , Ratas , Bloqueadores de los Canales de Potasio/uso terapéutico , Bloqueadores de los Canales de Potasio/farmacología , Bloqueadores de los Canales de Potasio/química , Bloqueadores de los Canales de Potasio/farmacocinética , Bloqueadores de los Canales de Potasio/síntesis química , Relación Estructura-Actividad , Canales de Potasio de Rectificación Interna/antagonistas & inhibidores , Canales de Potasio de Rectificación Interna/metabolismo , Descubrimiento de Drogas , Diuresis/efectos de los fármacos , Piperazinas/farmacología , Piperazinas/química , Piperazinas/uso terapéutico , Piperazinas/síntesis química , Piperazinas/farmacocinética , Masculino , Ratas Sprague-DawleyRESUMEN
While several farnesoid X receptor (FXR) agonists under clinical investigation for the treatment of nonalcoholic steatohepatitis (NASH) have shown beneficial effects, adverse effects such as pruritus and elevation of plasma lipids have limited their clinical efficacy and approvability. Herein, we report the discovery and preclinical evaluation of compound 32 (BMS-986339), a nonbile acid FXR agonist with a pharmacologically distinct profile relative to our previously reported agonist BMS-986318. Compound 32 exhibited potent in vitro and in vivo activation of FXR, albeit with a context-dependent profile that resulted in tissue-selective effects in vivo. To our knowledge, this is the first report that demonstrates differential induction of Fgf15 in the liver and ileum by FXR agonists in vivo. Compound 32 demonstrated robust antifibrotic efficacy despite reduced activation of certain genes in the liver, suggesting that the additional pharmacology of BMS-986318 does not further benefit efficacy, possibly presenting an opportunity for reduced adverse effects. Further evaluation in humans is warranted to validate this hypothesis.
