RESUMEN
With the aim to discover a gastric antisecretory agent more potent than the existing proton pump inhibitors, novel 3,4-dihydro-1H-spiro(naphthalene-2,2'-piperidin)-1-one derivatives, which could occupy two important lipophilic pockets (described as LP-1 and LP-2) of H+,K+-ATPase and can strongly bind to the K+-binding site, were designed based on a docking model. Among the compounds synthesized, compound 4d showed a strong H+,K+-ATPase-inhibitory activity and a high stomach concentration in rats, resulting in potent inhibitory action on histamine-stimulated gastric acid secretion in rats. Furthermore, 4d exerted significant inhibitory action on histamine-stimulated gastric-acid secretion in rats with a rapid onset and moderate duration of action after the administration. These findings may lead to a new insight into the drug design of potassium-competitive acid blockers.
Asunto(s)
ATPasa Intercambiadora de Hidrógeno-Potásio/metabolismo , Piperidinas/química , Potasio/metabolismo , Inhibidores de la Bomba de Protones/síntesis química , Compuestos de Espiro/química , Administración Intravenosa , Animales , Área Bajo la Curva , Sitios de Unión , Evaluación Preclínica de Medicamentos , Ácido Gástrico/metabolismo , Mucosa Gástrica/efectos de los fármacos , Mucosa Gástrica/metabolismo , ATPasa Intercambiadora de Hidrógeno-Potásio/química , Semivida , Histamina/toxicidad , Concentración 50 Inhibidora , Simulación del Acoplamiento Molecular , Naftalenos/química , Piperidinas/síntesis química , Piperidinas/farmacocinética , Potasio/química , Inhibidores de la Bomba de Protones/química , Inhibidores de la Bomba de Protones/farmacocinética , Curva ROC , Ratas , Compuestos de Espiro/síntesis química , Compuestos de Espiro/farmacocinética , Relación Estructura-ActividadRESUMEN
With the aim to discover a novel excellent potassium-competitive acid blocker (P-CAB) that could perfectly overcome the limitations of proton pump inhibitors (PPIs), we tested various approaches based on pyrrole derivative 1 as a lead compound. As part of a comprehensive approach to identify a new effective drug, we tried to optimize the duration of action of the pyrrole derivative. Among the compounds synthesized, fluoropyrrole derivative 20j, which has a 2-F-3-Py group at position 5, fluorine atom at position 4, and a 4-Me-2-Py sulfonyl group at the first position of the pyrrole ring, showed potent gastric acid-suppressive action and moderate duration of action in animal models. On the basis of structural properties including a slightly larger ClogP value (1.95), larger logD value (0.48) at pH 7.4, and fairly similar pKa value (8.73) compared to those of the previously optimized compound 2a, compound 20j was assumed to undergo rapid transfer to the stomach and have a moderate retention time there after single administration. Therefore, compound 20j was selected as a new promising P-CAB with moderately long duration of action.
Asunto(s)
Ácido Gástrico/metabolismo , ATPasa Intercambiadora de Hidrógeno-Potásio/metabolismo , Potasio/metabolismo , Inhibidores de la Bomba de Protones/farmacología , Pirroles/farmacología , Administración Oral , Animales , Relación Dosis-Respuesta a Droga , Humanos , Masculino , Estructura Molecular , Inhibidores de la Bomba de Protones/administración & dosificación , Inhibidores de la Bomba de Protones/química , Pirroles/administración & dosificación , Pirroles/química , Ratas , Ratas Sprague-Dawley , Relación Estructura-ActividadRESUMEN
With the aim to find a novel long-lasting potassium-competitive acid blocker (P-CAB) that would perfectly overcome the limitations of proton pump inhibitors (PPIs), we tried various approaches based on pyrrole derivative 1b as a lead compound. As part of a comprehensive approach to identification of a new drug, we explored excellent compounds that have low lipophilicity by introducing a polar hetero-aromatic group at position 5 of the pyrrole ring. Among the compounds synthesized, fluoropyrrole derivative 37c, which has a 2-F-3-Py group at the fifth position, lower pKa, and much lower ClogP and logD values than 1b dose, showed potent gastric-acid suppressive action resulting from gastric H+,K+-ATPase inhibition in animal models. Its maximum intragastric pH elevation effect was strong in rats, and its duration of action was much longer than that of either lansoprazole or lead compound 1b in dogs. Therefore, compound 37c can be considered a promising new P-CAB with long duration of action.
Asunto(s)
Canales de Potasio Éter-A-Go-Go/antagonistas & inhibidores , Ácido Gástrico/metabolismo , ATPasa Intercambiadora de Hidrógeno-Potásio/metabolismo , Inhibidores de la Bomba de Protones/farmacología , Pirroles/farmacología , Administración Oral , Animales , Supervivencia Celular/efectos de los fármacos , Perros , Relación Dosis-Respuesta a Droga , Canales de Potasio Éter-A-Go-Go/metabolismo , Células HEK293 , Células Hep G2 , Humanos , Concentración de Iones de Hidrógeno , Estructura Molecular , Inhibidores de la Bomba de Protones/administración & dosificación , Inhibidores de la Bomba de Protones/química , Pirroles/administración & dosificación , Pirroles/química , Ratas , Relación Estructura-ActividadRESUMEN
A series of 1H-pyrrolo[2,3-c]pyridine-7-amine derivatives were designed and synthesized based on our docking model as potassium-competitive acid blockers (P-CABs). Molecular modeling of these derivatives led us to introduce a substituent at the 1-position to access two lipophilic sites and polar residues. We identified potent P-CABs that exhibit excellent inhibitory activity in vitro and in vivo. These results indicate that the 1H-pyrrolo[2,3-c]pyridine-7-amine derivatives are promising lead compounds as P-CABs.
Asunto(s)
Modelos Moleculares , Potasio , Inhibidores de la Bomba de Protones/química , Inhibidores de la Bomba de Protones/farmacología , Animales , Química Farmacéutica/métodos , Diseño de Fármacos , Evaluación Preclínica de Medicamentos/métodos , Ácido Gástrico/metabolismo , ATPasa Intercambiadora de Hidrógeno-Potásio/metabolismo , Histamina/farmacología , Masculino , Inhibidores de la Bomba de Protones/síntesis química , Piridinas/química , Ratas , Ratas Sprague-Dawley , Relación Estructura-ActividadRESUMEN
To discover a gastric antisecretory agent more potent than existing proton pump inhibitors, novel pyrrole derivatives were synthesized, and their H(+),K(+)-ATPase inhibitory activities and inhibitory action on histamine-stimulated gastric acid secretion in rats were evaluated. Among the compounds synthesized, compound 17a exhibited selective and potent H(+),K(+)-ATPase inhibitory activity through reversible and K(+)-competitive ionic binding; furthermore, compound 17c exhibited potent inhibitory action on histamine-stimulated gastric acid secretion in rats and Heidenhain pouch dogs.
Asunto(s)
Descubrimiento de Drogas , Inhibidores de la Bomba de Protones , Pirroles/síntesis química , Pirroles/farmacología , Animales , Perros , ATPasa Intercambiadora de Hidrógeno-Potásio/metabolismo , Masculino , Modelos Moleculares , Estructura Molecular , Pirroles/química , Ratas , Ratas Sprague-Dawley , Estómago/enzimología , Relación Estructura-Actividad , PorcinosRESUMEN
In our pursuit of developing a novel and potent potassium-competitive acid blocker (P-CAB), we synthesized pyrrole derivatives focusing on compounds with low log D and high ligand-lipophilicity efficiency (LLE) values. Among the compounds synthesized, the compound 13e exhibited potent H(+),K(+)-ATPase inhibitory activity and potent gastric acid secretion inhibitory action in vivo. Its maximum efficacy was more potent and its duration of action was much longer than those of proton pump inhibitors (PPIs). Therefore, compound 13e (1-[5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]-N-methylmethanamine fumarate, TAK-438) was selected as a drug candidate for the treatment of gastroesophageal reflux disease (GERD), peptic ulcer, and other acid-related diseases.
Asunto(s)
Antiulcerosos/química , Antiulcerosos/farmacología , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacología , Inhibidores de la Bomba de Protones , Pirroles/química , Pirroles/farmacología , Sulfonamidas/química , Sulfonamidas/farmacología , Animales , Antiulcerosos/síntesis química , Antiulcerosos/farmacocinética , Perros , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/farmacocinética , Fumaratos/síntesis química , Fumaratos/química , Fumaratos/farmacocinética , Mucosa Gástrica/efectos de los fármacos , Mucosa Gástrica/metabolismo , ATPasa Intercambiadora de Hidrógeno-Potásio/metabolismo , Humanos , Concentración 50 Inhibidora , Espectroscopía de Resonancia Magnética , Masculino , Estructura Molecular , Úlcera Péptica/tratamiento farmacológico , Úlcera Péptica/metabolismo , Pirroles/síntesis química , Ratas , Ratas Sprague-Dawley , Relación Estructura-Actividad , Sulfonamidas/síntesis químicaRESUMEN
Proton pump inhibitors (PPIs) are widely used for the treatment of acid-related diseases. However, several medical needs such as suppression of night-time acid secretion and rapid symptom relief remain unmet. In this study, we investigated the effects of 1-[5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]-N-methylmethanamine monofumarate (TAK-438), a novel potassium-competitive acid blocker, on acid secretion in rats and dogs under various conditions, in comparison with the PPI lansoprazole [2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl] methyl]sulfinyl]-1H-benzimidazole], to characterize the antisecretory action of TAK-438. TAK-438 showed a more potent and longer-lasting inhibitory effect than lansoprazole on the histamine-stimulated gastric acid secretion in rats and dogs. A pharmacokinetic study in rats showed that TAK-438 accumulated and was retained in the gastric tissue for more than 24 h, unlike that in the plasma. TAK-438 showed significant antisecretory activity with or without cimetidine pretreatment, in contrast to lansoprazole, which did not show antisecretory activity after cimetidine pretreatment in rats. TAK-438 increased the pH of the gastric perfusate to 5.7 in an unstimulated condition, and this effect was maintained in the presence of subsequent histamine stimulation. On the other hand, lansoprazole also increased the pH in an unstimulated condition, but this effect diminished after histamine stimulation. These results indicated that TAK-438 exerted a more potent and longer-lasting antisecretory effect than lansoprazole through high accumulation and slow clearance from the gastric tissue. In addition, TAK-438 was unaffected by the gastric secretory state, unlike PPIs. Therefore, TAK-438 can provide a novel mechanism of action to improve the present PPI-based treatment of acid-related diseases.
Asunto(s)
2-Piridinilmetilsulfinilbencimidazoles/farmacología , Antiulcerosos/farmacología , Ácido Gástrico/metabolismo , Inhibidores de la Bomba de Protones/farmacología , Pirroles/farmacología , Sulfonamidas/farmacología , Animales , Antiulcerosos/sangre , Antiulcerosos/farmacocinética , Cimetidina/farmacología , Perros , Mucosa Gástrica/efectos de los fármacos , Mucosa Gástrica/metabolismo , ATPasa Intercambiadora de Hidrógeno-Potásio/metabolismo , Histamina/farmacología , Agonistas de los Receptores Histamínicos/farmacología , Concentración de Iones de Hidrógeno , Lansoprazol , Masculino , Potasio/metabolismo , Pirroles/sangre , Pirroles/farmacocinética , Ratas , Ratas Sprague-Dawley , Sulfonamidas/sangre , Sulfonamidas/farmacocinética , Factores de TiempoRESUMEN
TAK-438 is a novel potassium-competitive acid blocker (P-CAB) type antisecretory agent that reversibly inhibits gastric H+, K+-ATPase. Previously, we showed that TAK-438 has superior efficacy compared to lansoprazole, a proton pump inhibitor, in the inhibition of acid secretion in vivo. In this study, we investigated the differences in the mode of actions of the two drugs using primary cultured rabbit gastric glands. TAK-438 and lansoprazole inhibited gastric acid formation in acutely isolated gastric glands (IC50) values, 0.30 and 0.76 µM, respectively). In cultured gastric glands that were preincubated with TAK-438, the inhibitory effect on forskolin-stimulated acid formation was augmented over the incubation period, whereas the inhibitory effect of lansoprazole was not affected by time of incubation. Next, we evaluated the durations of the actions of TAK-438 and lansoprazole after gastric glands were incubated with either drug for 2h followed by washout. Even 8h after the drug washout, TAK-438 at higher concentrations inhibited acid formation, but the inhibitory effect of lansoprazole disappeared immediately after washout. Additionally, only a small amount of [¹4C] lansoprazole accumulated in resting glands, and this accumulation was enhanced by treatment with 1 µM of forskolin. In contrast, high levels of [¹4C] TAK-438 accumulated in both resting and forskolin-treated glands. Furthermore, a 2-h preincubation followed by washout demonstrated a slow clearance of [¹4C] TAK-438 from the glands. These findings suggest that TAK-438 exerts a longer and more potent antisecretory effect than lansoprazole as a result of its high accumulation and slow clearance from the gastric glands.
Asunto(s)
2-Piridinilmetilsulfinilbencimidazoles/farmacología , Antiulcerosos/farmacología , Potasio/metabolismo , Pirroles/farmacología , Estómago/efectos de los fármacos , Sulfonamidas/farmacología , Animales , Células Cultivadas , ATPasa Intercambiadora de Hidrógeno-Potásio/metabolismo , Lansoprazol , Inhibidores de la Bomba de Protones , Conejos , Estómago/citologíaRESUMEN
Proton pump inhibitors (PPIs) are widely used in the treatment of acid-related diseases. However, several unmet medical needs, such as suppression of night-time acid secretion and rapid symptom relief, remain. In this study, we investigated the pharmacological effects of 1-[5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]-N-methylmethanamine monofumarate (TAK-438), a novel potassium-competitive acid blocker (P-CAB), on gastric acid secretion in comparison with lansoprazole, a typical PPI, and SCH28080 [3-(cyanomethyl)-2-methyl,8-(phenylmethoxy)imidazo(1,2-a)pyridine], a prototype of P-CAB. TAK-438, SCH28080, and lansoprazole inhibited H(+),K(+)-ATPase activity in porcine gastric microsomes with IC(50) values of 0.019, 0.14, and 7.6 µM, respectively, at pH 6.5. The inhibitory activity of TAK-438 was unaffected by ambient pH, whereas the inhibitory activities of SCH28080 and lansoprazole were weaker at pH 7.5. The inhibition by TAK-438 and SCH28080 was reversible and achieved in a K(+)-competitive manner, quite different from that by lansoprazole. TAK-438, at a dose of 4 mg/kg (as the free base) orally, completely inhibited basal and 2-deoxy-d-glucose-stimulated gastric acid secretion in rats, and its effect on both was stronger than that of lansoprazole. TAK-438 increased the pH of gastric perfusate to a higher value than did lansoprazole or SCH28080, and the effect of TAK-438 was sustained longer than that of lansoprazole or SCH28080. These results indicate that TAK-438 exerts a more potent and longer-lasting inhibitory action on gastric acid secretion than either lansoprazole or SCH28080. TAK-438 is a novel antisecretory drug that may provide a new option for the patients with acid-related disease that is refractory to, or inadequately controlled by, treatment with PPIs.