RESUMEN
Following the discovery of small molecule acyl piperazine ROMK inhibitors and their initial preclinical validation as a novel diuretic agent, our group set out to discover new ROMK inhibitors with reduced risk for QT effects, suitable for further pharmacological experiments in additional species. Several strategies for decreasing hERG affinity while maintaining ROMK inhibition were investigated and are described herein. The most promising candidate, derived from the newly discovered 4-N-heteroaryl acetyl series, improved functional hERG/ROMK ratio by >10× over the previous lead. In vivo evaluation demonstrated comparable diuretic effects in rat with no detectable QT effects at the doses evaluated in an in vivo dog model.
Asunto(s)
Canal de Potasio ERG1/fisiología , Compuestos Heterocíclicos/farmacología , Piperazinas/farmacología , Compuestos Heterocíclicos/química , Piperazinas/química , Relación Estructura-ActividadRESUMEN
Following the discovery of small molecule acyl piperazine ROMK inhibitors, the acyl octahydropyrazino[2,1-c][1,4]oxazine series was identified. This series displays improved ROMK/hERG selectivity, and as a consequence, the resulting ROMK inhibitors do not evoke QTc prolongation in an in vivo cardiovascular dog model. Further efforts in this series led to the discovery of analogs with improved pharmacokinetic profiles. This new series also retained comparable ROMK potency compared to earlier leads.
Asunto(s)
Oxazinas/química , Oxazinas/farmacología , Canales de Potasio de Rectificación Interna/antagonistas & inhibidores , Animales , Diuresis/efectos de los fármacos , Perros , Insuficiencia Cardíaca/tratamiento farmacológico , Humanos , Hipertensión/tratamiento farmacológico , Macaca mulatta , Oxazinas/farmacocinética , Canales de Potasio de Rectificación Interna/metabolismo , Ratas Sprague-Dawley , Regulador Transcripcional ERG/antagonistas & inhibidores , Regulador Transcripcional ERG/metabolismoRESUMEN
The renal outer medullary potassium (ROMK) channel, which is located at the apical membrane of epithelial cells lining the thick ascending loop of Henle and cortical collecting duct, plays an important role in kidney physiology by regulating salt reabsorption. Loss-of-function mutations in the human ROMK channel are associated with antenatal type II Bartter's syndrome, an autosomal recessive life-threatening salt-wasting disorder with mild hypokalemia. Similar observations have been reported from studies with ROMK knockout mice and rats. It is noteworthy that heterozygous carriers of Kir1.1 mutations associated with antenatal Bartter's syndrome have reduced blood pressure and a decreased risk of developing hypertension by age 60. Although selective ROMK inhibitors would be expected to represent a new class of diuretics, this hypothesis has not been pharmacologically tested. Compound A [5-(2-(4-(2-(4-(1H-tetrazol-1-yl)phenyl)acetyl)piperazin-1-yl)ethyl)isobenzofuran-1(3H)-one)], a potent ROMK inhibitor with appropriate selectivity and characteristics for in vivo testing, has been identified. Compound A accesses the channel through the cytoplasmic side and binds to residues lining the pore within the transmembrane region below the selectivity filter. In normotensive rats and dogs, short-term oral administration of compound A caused concentration-dependent diuresis and natriuresis that were comparable to hydrochlorothiazide. Unlike hydrochlorothiazide, however, compound A did not cause any significant urinary potassium losses or changes in plasma electrolyte levels. These data indicate that pharmacologic inhibition of ROMK has the potential for affording diuretic/natriuretic efficacy similar to that of clinically used diuretics but without the dose-limiting hypokalemia associated with the use of loop and thiazide-like diuretics.
Asunto(s)
Diuresis/efectos de los fármacos , Diuresis/fisiología , Natriuresis/efectos de los fármacos , Bloqueadores de los Canales de Potasio/farmacología , Canales de Potasio de Rectificación Interna/antagonistas & inhibidores , Canales de Potasio de Rectificación Interna/fisiología , Animales , Células CHO , Cricetinae , Cricetulus , Perros , Relación Dosis-Respuesta a Droga , Femenino , Células HEK293 , Humanos , Células de Riñón Canino Madin Darby , Masculino , Natriuresis/fisiología , Ratas , Ratas Sprague-DawleyRESUMEN
A new series of thiazole-substituted 1,1,1,3,3,3-hexafluoro-2-propanols were prepared and evaluated as malonyl-CoA decarboxylase (MCD) inhibitors. Key analogs caused dose-dependent decreases in food intake and body weight in obese mice. Acute treatment with these compounds also led to a drop in elevated blood glucose in a murine model of type II diabetes.
Asunto(s)
Fármacos Antiobesidad/uso terapéutico , Carboxiliasas/antagonistas & inhibidores , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Diseño de Fármacos , Hipoglucemiantes/uso terapéutico , Obesidad/tratamiento farmacológico , Propanoles/uso terapéutico , Animales , Fármacos Antiobesidad/síntesis química , Fármacos Antiobesidad/química , Fármacos Antiobesidad/farmacología , Glucemia/efectos de los fármacos , Peso Corporal/efectos de los fármacos , Carboxiliasas/metabolismo , Ingestión de Alimentos/efectos de los fármacos , Humanos , Hipoglucemiantes/síntesis química , Hipoglucemiantes/química , Hipoglucemiantes/farmacología , Ratones , Ratones Endogámicos C57BL , Propanoles/síntesis química , Propanoles/química , Propanoles/farmacología , Tiazoles/síntesis química , Tiazoles/química , Tiazoles/farmacología , Tiazoles/uso terapéuticoRESUMEN
The renal outer medullary potassium channel (ROMK or Kir1.1) is a putative drug target for a novel class of diuretics that could be used for the treatment of hypertension and edematous states such as heart failure. An internal high-throughput screening campaign identified 1,4-bis(4-nitrophenethyl)piperazine (5) as a potent ROMK inhibitor. It is worth noting that this compound was identified as a minor impurity in a screening hit that was responsible for all of the initially observed ROMK activity. Structure-activity studies resulted in analogues with improved rat pharmacokinetic properties and selectivity over the hERG channel, providing tool compounds that can be used for in vivo pharmacological assessment. The featured ROMK inhibitors were also selective against other members of the inward rectifier family of potassium channels.