RESUMEN
A renal outer medullary potassium channel (ROMK, Kir1.1) is a putative drug target for a novel class of diuretics with potential for treating hypertension and heart failure. Our first disclosed clinical ROMK compound, 2 (MK-7145), demonstrated robust diuresis, natriuresis, and blood pressure lowering in preclinical models, with reduced urinary potassium excretion compared to the standard of care diuretics. However, 2 projected to a short human half-life (â¼5 h) that could necessitate more frequent than once a day dosing. In addition, a short half-life would confer a high peak-to-trough ratio which could evoke an excessive peak diuretic effect, a common liability associated with loop diuretics such as furosemide. This report describes the discovery of a new ROMK inhibitor 22e (MK-8153), with a longer projected human half-life (â¼14 h), which should lead to a reduced peak-to-trough ratio, potentially extrapolating to more extended and better tolerated diuretic effects.
Asunto(s)
Natriuréticos/química , Bloqueadores de los Canales de Potasio/química , Canales de Potasio de Rectificación Interna/antagonistas & inhibidores , Potenciales de Acción/efectos de los fármacos , Animales , Benzofuranos/química , Presión Sanguínea/efectos de los fármacos , Diuréticos/química , Diuréticos/metabolismo , Diuréticos/farmacología , Perros , Semivida , Haplorrinos , Humanos , Masculino , Natriuréticos/metabolismo , Natriuréticos/farmacología , Piperazinas/química , Potasio/orina , Bloqueadores de los Canales de Potasio/metabolismo , Bloqueadores de los Canales de Potasio/farmacología , Canales de Potasio de Rectificación Interna/metabolismo , Ratas , Ratas Endogámicas SHRRESUMEN
The NO-sGC-cGMP signaling pathway plays an important role in the cardiovascular system. Loss of nitric oxide tone or impaired signaling has been associated with cardiovascular diseases, such as hypertension, pulmonary hypertension and heart failure. Direct activation of sGC enzyme independent of NO represents a novel approach for modulating NO signaling with tremendous therapeutic potential. Herein, we describe the design of a structurally novel class of heme-dependent sGC stimulators containing the 3,3-dimethylpyrrolidin-2-one moiety which resulted in the identification of the potent, selective stimulator 30 (MK-2947) for the treatment of hypertension.
Asunto(s)
Antihipertensivos/farmacología , Descubrimiento de Drogas , Hipertensión/tratamiento farmacológico , Guanilil Ciclasa Soluble/metabolismo , Antihipertensivos/química , Relación Dosis-Respuesta a Droga , Humanos , Estructura Molecular , Relación Estructura-ActividadRESUMEN
SAR in the previously described spirocyclic ROMK inhibitor series was further evolved from lead 4 by modification of the spirocyclic core and identification of novel right-side pharmacophores. In this process, it was discovered that the spiropyrrolidinone core with the carbonyl group α to the spirocenter was preferred for potent ROMK activity. Efforts aimed at decreasing hERG affinity within the series led to the discovery of multiple novel right-hand pharmacophores including 3-methoxythiadiazole, 2-methoxypyrimidine, and pyridazinone. The most promising candidate is pyridazinone analog 32 that showed an improved functional hERG/ROMK potency ratio and preclinical PK profile. In vivo evaluation of 32 demonstrated blood pressure lowering effects in the spontaneously hypertensive rat model.
Asunto(s)
Canal de Potasio ERG1/metabolismo , Bloqueadores de los Canales de Potasio/química , Canales de Potasio de Rectificación Interna/antagonistas & inhibidores , Animales , Modelos Animales de Enfermedad , Perros , Canal de Potasio ERG1/antagonistas & inhibidores , Semivida , Hipertensión/tratamiento farmacológico , Bloqueadores de los Canales de Potasio/farmacocinética , Bloqueadores de los Canales de Potasio/uso terapéutico , Canales de Potasio de Rectificación Interna/metabolismo , Pirimidinas/química , Ratas , Ratas Endogámicas SHR , Compuestos de Espiro/química , Relación Estructura-Actividad , Tiadiazoles/químicaRESUMEN
A spirocyclic class of ROMK inhibitors was developed containing a structurally diverse heterocyclic sulfone moiety and spirocyclic core starting from lead 1. These compounds not only displayed exquisite ROMK potency but significantly improved selectivity over hERG. The lead compounds were found to have favorable pharmacokinetic properties and displayed robust diuretic, natriuretic and blood pressure lowering effects in spontaneously hypertensive rats.
Asunto(s)
Diuréticos/farmacología , Diseño de Fármacos , Inhibidores Enzimáticos/farmacología , Compuestos Heterocíclicos/química , Compuestos Heterocíclicos/farmacología , Canales de Potasio de Rectificación Interna/antagonistas & inhibidores , Sulfonas/farmacología , Animales , Compuestos Heterocíclicos/síntesis química , Ratas , Ratas Endogámicas SHRRESUMEN
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
ROMK, the renal outer medullary potassium channel, is involved in potassium recycling at the thick ascending loop of Henle and potassium secretion at the cortical collecting duct in the kidney nephron. Because of this dual site of action, selective inhibitors of ROMK are expected to represent a new class of diuretics/natriuretics with superior efficacy and reduced urinary loss of potassium compared to standard-of-care loop and thiazide diuretics. Following our earlier work, this communication will detail subsequent medicinal chemistry endeavors to further improve lead selectivity against the hERG channel and preclinical pharmacokinetic properties. Pharmacological assessment of highlighted inhibitors will be described, including pharmacodynamic studies in both an acute rat diuresis/natriuresis model and a subchronic blood pressure model in spontaneous hypertensive rats. These proof-of-biology studies established for the first time that the human and rodent genetics accurately predict the in vivo pharmacology of ROMK inhibitors and supported identification of the first small molecule ROMK inhibitor clinical candidate, MK-7145.
RESUMEN
The renal outer medullary potassium (ROMK) channel, located at the apical surface of epithelial cells in the thick ascending loop of Henle and cortical collecting duct, contributes to salt reabsorption and potassium secretion, and represents a target for the development of new mechanism of action diuretics. This idea is supported by the phenotype of antenatal Bartter's syndrome type II associated with loss-of-function mutations in the human ROMK channel, as well as, by cardiovascular studies of heterozygous carriers of channel mutations associated with type II Bartter's syndrome. Although the pharmacology of ROMK channels is still being developed, channel inhibitors have been identified and shown to cause natriuresis and diuresis, in the absence of any significant kaliuresis, on acute oral dosing to rats or dogs. Improvements in potency and selectivity have led to the discovery of MK-7145 [5,5'-((1R,1'R)-piperazine-1,4-diylbis(1-hydroxyethane-2,1-diyl))bis(4-methylisobenzofuran-1(3H)-one)], a potential clinical development candidate. In spontaneously hypertensive rats, oral dosing of MK-7145 causes dose-dependent lowering of blood pressure that is maintained during the entire treatment period, and that displays additive/synergistic effects when administered in combination with hydrochlorothiazide or candesartan, respectively. Acute or chronic oral administration of MK-7145 to normotensive dogs led to dose-dependent diuresis and natriuresis, without any significant urinary potassium losses or changes in plasma electrolyte levels. Elevations in bicarbonate and aldosterone were found after 6 days of dosing. These data indicate that pharmacological inhibition of ROMK has potential as a new mechanism for the treatment of hypertension and/or congestive heart failure. In addition, Bartter's syndrome type II features are manifested on exposure to ROMK inhibitors.
Asunto(s)
Síndrome de Bartter/fisiopatología , Benzofuranos/farmacología , Presión Sanguínea/efectos de los fármacos , Fenotipo , Piperazinas/farmacología , Bloqueadores de los Canales de Potasio/farmacología , Canales de Potasio de Rectificación Interna/antagonistas & inhibidores , Animales , Síndrome de Bartter/tratamiento farmacológico , Bencimidazoles/farmacología , Benzofuranos/uso terapéutico , Compuestos de Bifenilo , Perros , Relación Dosis-Respuesta a Droga , Sinergismo Farmacológico , Femenino , Células HEK293 , Humanos , Hidroclorotiazida/farmacología , Masculino , Piperazinas/uso terapéutico , Bloqueadores de los Canales de Potasio/uso terapéutico , Ratas , Tetrazoles/farmacologíaRESUMEN
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
Hit-to-lead efforts resulted in the discovery of compound 19, a potent CYP11B2 inhibitor that displays high selectivity vs related CYPs, good pharmacokinetic properties in rat and rhesus, and lead-like physical properties. In a rhesus pharmacodynamic model, compound 19 displays robust, dose-dependent aldosterone lowering efficacy, with no apparent effect on cortisol levels.
RESUMEN
A new subseries of ROMK inhibitors exemplified by 28 has been developed from the initial screening hit 1. The excellent selectivity for ROMK inhibition over related ion channels and pharmacokinetic properties across preclinical species support further preclinical evaluation of 28 as a new mechanism diuretic. Robust pharmacodynamic effects in both SD rats and dogs have been demonstrated.
RESUMEN
We report the discovery of a benzimidazole series of CYP11B2 inhibitors. Hit-to-lead and lead optimization studies identified compounds such as 32, which displays potent CYP11B2 inhibition, high selectivity versus related CYP targets, and good pharmacokinetic properties in rat and rhesus. In a rhesus pharmacodynamic model, 32 produces dose-dependent aldosterone lowering efficacy, with no apparent effect on cortisol levels.
RESUMEN
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 sub-class of distinct small molecule ROMK inhibitors were developed from the original lead 1. Medicinal chemistry endeavors led to novel ROMK inhibitors with good ROMK functional potency and improved hERG selectivity. Two of the described ROMK inhibitors were characterized for the first in vivo proof-of-concept biology studies, and results from an acute rat diuresis model confirmed the hypothesis that ROMK inhibitors represent new mechanism diuretic and natriuretic agents.
Asunto(s)
Benzofuranos/química , Benzofuranos/farmacología , Canales de Potasio de Rectificación Interna/antagonistas & inhibidores , Animales , Benzofuranos/farmacocinética , Diuresis/efectos de los fármacos , Descubrimiento de Drogas , Canales de Potasio Éter-A-Go-Go/antagonistas & inhibidores , Canales de Potasio Éter-A-Go-Go/metabolismo , Humanos , Canales de Potasio de Rectificación Interna/metabolismo , Ratas , Ratas Sprague-Dawley , Tetrazoles/química , Tetrazoles/farmacocinética , Tetrazoles/farmacologíaRESUMEN
In an effort to understand the origin of blood-pressure lowering effects observed in recent clinical trials with 11ß-HSD1 inhibitors, we examined a set of 11ß-HSD1 inhibitors in a series of relevant in vitro and in vivo assays. Select 11ß-HSD1 inhibitors reduced blood pressure in our preclinical models but most or all of the blood pressure lowering may be mediated by a 11ß-HSD1 independent pathway.
Asunto(s)
11-beta-Hidroxiesteroide Deshidrogenasa de Tipo 1/antagonistas & inhibidores , Inhibidores Enzimáticos/farmacología , Hipertensión/tratamiento farmacológico , Hipertensión/enzimología , Triazoles/farmacología , Animales , Humanos , Ratones , Ratones Noqueados , Ratas , Ratas Endogámicas SHRRESUMEN
4-Substituted piperidine-derived trisubstituted ureas are reported as highly potent and selective inhibitors for sEH. The SAR outlines approaches to improve activity against sEH and reduce ion channel and CYP liability. With minimal off-target activity and a good PK profile, the benchmark 2d exhibited remarkable in vitro and ex vivo target engagement. The eutomer entA-2d also elicited vasodilation effect in rat mesenteric artery.
Asunto(s)
Epóxido Hidrolasas/antagonistas & inhibidores , Piperidinas/síntesis química , Urea/análogos & derivados , Urea/síntesis química , Animales , Disponibilidad Biológica , Línea Celular , Cristalografía por Rayos X , Inhibidores Enzimáticos del Citocromo P-450 , Sistema Enzimático del Citocromo P-450/metabolismo , Eicosanoides/metabolismo , Compuestos Epoxi/metabolismo , Humanos , Técnicas In Vitro , Canales Iónicos/antagonistas & inhibidores , Canales Iónicos/metabolismo , Riñón/efectos de los fármacos , Riñón/metabolismo , Arterias Mesentéricas/efectos de los fármacos , Arterias Mesentéricas/fisiología , Modelos Moleculares , Conformación Molecular , Relajación Muscular , Músculo Liso Vascular/efectos de los fármacos , Músculo Liso Vascular/fisiología , Piperidinas/farmacocinética , Piperidinas/farmacología , Ratas , Ratas Endogámicas SHR , Solubilidad , Estereoisomerismo , Relación Estructura-Actividad , Urea/farmacocinética , Urea/farmacologíaRESUMEN
Distinct from previously reported urea and amide inhibitors of soluble epoxide hydrolase (sEH), a novel class of inhibitors were rationally designed based on the X-ray structure of this enzyme and known amide inhibitors. The structure-activity relationship (SAR) study was focused on improving the sEH inhibitory activity. Aminobenzisoxazoles emerged to be the optimal series, of which a potent human sEH inhibitor 7t was identified with a good pharmacokinetics (PK) profile. The strategy of employing aminoheterocycles as amide replacements may represent a general approach to develop mimics of known hydrolase or protease inhibitors containing an amide moiety.
Asunto(s)
Amidas/química , Compuestos de Anilina/química , Inhibidores Enzimáticos/química , Epóxido Hidrolasas/antagonistas & inhibidores , Compuestos Heterocíclicos con 2 Anillos/química , Isoxazoles/química , Compuestos de Anilina/síntesis química , Compuestos de Anilina/farmacocinética , Animales , Sitios de Unión , Simulación por Computador , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/farmacocinética , Epóxido Hidrolasas/metabolismo , Compuestos Heterocíclicos con 2 Anillos/síntesis química , Compuestos Heterocíclicos con 2 Anillos/farmacocinética , Humanos , Isoxazoles/síntesis química , Isoxazoles/farmacocinética , Unión Proteica , Ratas , Relación Estructura-ActividadRESUMEN
3,3-Disubstituted piperidine-derived trisubstituted urea entA-2b was discovered as a highly potent and selective soluble epoxide hydrolase (sEH) inhibitor. Despite the good compound oral exposure, excellent sEH inhibition in whole blood, and remarkable selectivity, compound entA-2b failed to lower blood pressure acutely in spontaneously hypertensive rats (SHRs). This observation further challenges the premise that sEH inhibition can provide a viable approach to the treatment of hypertensive patients.
Asunto(s)
Epóxido Hidrolasas/antagonistas & inhibidores , Epóxido Hidrolasas/metabolismo , Hipertensión/tratamiento farmacológico , Piperidinas/química , Urea/análogos & derivados , Urea/farmacología , Ácido 8,11,14-Eicosatrienoico/análogos & derivados , Ácido 8,11,14-Eicosatrienoico/sangre , Ácido 8,11,14-Eicosatrienoico/metabolismo , Animales , Presión Sanguínea/efectos de los fármacos , Humanos , Modelos Moleculares , Unión Proteica , Ratas , Ratas Endogámicas SHR , Relación Estructura-Actividad , Urea/uso terapéuticoRESUMEN
Spirocyclic secondary amine-derived trisubstituted ureas were identified as highly potent, bioavailable and selective soluble epoxide hydrolase (sEH) inhibitors. Despite good oral exposure and excellent ex vivo target engagement in blood, one such compound, rac-1a, failed to lower blood pressure acutely in spontaneously hypertensive rats (SHRs). This study posed the question as to whether sEH inhibition provides a robust mechanism leading to a significant antihypertensive effect.
Asunto(s)
Aminas/química , Antihipertensivos/síntesis química , Inhibidores Enzimáticos/síntesis química , Epóxido Hidrolasas/antagonistas & inhibidores , Compuestos de Espiro/química , Urea/análogos & derivados , Animales , Antihipertensivos/química , Antihipertensivos/farmacocinética , Línea Celular , Descubrimiento de Drogas , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacocinética , Epóxido Hidrolasas/metabolismo , Humanos , Ratas , Ratas Endogámicas SHR , Relación Estructura-Actividad , Urea/síntesis química , Urea/farmacocinéticaRESUMEN
A novel class of indole ligands for estrogen receptor alpha have been discovered which exhibit potent affinity and high selectivity. Substitution of the bazedoxifene skeleton to the linker present in the HTS lead 1a provided 22b which was found to be 130-fold alpha-selective and acted as an antagonist of estradiol activity in uterine tissue and MCF-7 cancer cells.
Asunto(s)
Receptor alfa de Estrógeno/antagonistas & inhibidores , Indoles/química , Indoles/farmacocinética , Neoplasias de la Mama/tratamiento farmacológico , Línea Celular Tumoral , Antagonistas de Estrógenos/química , Antagonistas de Estrógenos/farmacología , Femenino , Humanos , Concentración 50 Inhibidora , Ligandos , Útero/efectos de los fármacosRESUMEN
Two novel side chains which had previously been found to enhance antagonist activity in the dihydrobenzoxathiin SERM series were applied to three existing platforms. The novel side chains did not improve the antagonist activity of the existing platforms.