RESUMEN
Janus kinases (JAKs) are considered promising targets for the treatment of autoimmune diseases including rheumatoid arthritis (RA) due to their important role in multiple cytokine receptor signaling pathways. Recently, several JAK inhibitors have been developed for the treatment of RA. Here, we describe the identification of the novel orally bioavailable JAK inhibitor 18, peficitinib (also known as ASP015K), which showed moderate selectivity for JAK3 over JAK1, JAK2, and TYK2 in enzyme assays. Chemical modification at the C4-position of lead compound 5 led to a large increase in JAK inhibitory activity and metabolic stability in liver microsomes. Furthermore, we determined the crystal structures of JAK1, JAK2, JAK3, and TYK2 in a complex with peficitinib, and revealed that the 1H-pyrrolo[2,3-b]pyridine-5-carboxamide scaffold of peficitinib forms triple hydrogen bonds with the hinge region. Interestingly, the binding modes of peficitinib in the ATP-binding pockets differed among JAK1, JAK2, JAK3, and TYK2. WaterMap analysis of the crystal structures suggests that unfavorable water molecules are the likely reason for the difference in orientation of the 1H-pyrrolo[2,3-b]pyridine-5-carboxamide scaffold to the hinge region among JAKs.
Asunto(s)
Adamantano/análogos & derivados , Descubrimiento de Drogas , Inhibidores de las Cinasas Janus/química , Inhibidores de las Cinasas Janus/farmacología , Niacinamida/análogos & derivados , Adamantano/química , Adamantano/farmacocinética , Adamantano/farmacología , Adamantano/uso terapéutico , Administración Oral , Animales , Artritis Reumatoide/tratamiento farmacológico , Disponibilidad Biológica , Humanos , Inhibidores de las Cinasas Janus/farmacocinética , Inhibidores de las Cinasas Janus/uso terapéutico , Ratones , Niacinamida/química , Niacinamida/farmacocinética , Niacinamida/farmacología , Niacinamida/uso terapéutico , Ratas , Relación Estructura-ActividadRESUMEN
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
Janus kinases (JAKs) regulate various inflammatory and immune responses and are targets for the treatment of inflammatory and immune diseases. As a novel class of immunomodulators targeting JAK3, 1H-pyrrolo[2,3-b]pyridine-5-carboxamide derivatives are promising candidates for treating such diseases. In chemical modification of lead compound 2, the substitution of a cycloalkyl ring for an N-cyanopyridylpiperidine in C4-position was effective for increasing JAK3 inhibitory activity. In addition, modulation of physical properties such as molecular lipophilicity and basicity was important for reducing human ether-a-go-go-related gene (hERG) inhibitory activity. Our optimization study gave compound 31, which exhibited potent JAK3 inhibitory activity as well as weak hERG inhibitory activity. In cellular assay, 31 exhibited potent immunomodulating effect on IL-2-stimulated T cell proliferation. In a pharmacokinetic study, good metabolic stability and oral bioavailability of 31 were achieved in rats, dogs, and monkeys. Further, 31 prolonged graft survival in an in vivo rat heterotopic cardiac transplant model.
Asunto(s)
Amidas/química , Factores Inmunológicos/síntesis química , Janus Quinasa 3/antagonistas & inhibidores , Inhibidores de Proteínas Quinasas/síntesis química , Administración Oral , Amidas/farmacocinética , Amidas/uso terapéutico , Animales , Sitios de Unión , Proliferación Celular/efectos de los fármacos , Perros , Rechazo de Injerto/prevención & control , Semivida , Haplorrinos , Humanos , Factores Inmunológicos/farmacología , Factores Inmunológicos/uso terapéutico , Interleucina-2/metabolismo , Janus Quinasa 1/antagonistas & inhibidores , Janus Quinasa 1/metabolismo , Janus Quinasa 2/antagonistas & inhibidores , Janus Quinasa 2/metabolismo , Janus Quinasa 3/metabolismo , Masculino , Microsomas Hepáticos/metabolismo , Simulación del Acoplamiento Molecular , Inhibidores de Proteínas Quinasas/farmacocinética , Inhibidores de Proteínas Quinasas/uso terapéutico , Estructura Terciaria de Proteína , Piridinas/química , Ratas , Ratas Endogámicas Lew , Linfocitos T/citología , Linfocitos T/efectos de los fármacos , Linfocitos T/metabolismo , Trasplante HeterotópicoRESUMEN
Janus kinases (JAKs) have been known to play crucial roles in modulating a number of inflammatory and immune mediators. Here, we describe a series of 1H-pyrrolo[2,3-b]pyridine derivatives as novel immunomodulators targeting JAK3 for use in treating immune diseases such as organ transplantation. In the chemical modification of compound 6, the introduction of a carbamoyl group to the C5-position and substitution of a cyclohexylamino group at the C4-position of the 1H-pyrrolo[2,3-b]pyridine ring led to a large increase in JAK3 inhibitory activity. Compound 14c was identified as a potent, moderately selective JAK3 inhibitor, and the immunomodulating effect of 14c on interleukin-2-stimulated T cell proliferation was shown. Docking calculations and WaterMap analysis of the 1H-pyrrolo[2,3-b]pyridine-5-carboxamide derivatives were conducted to confirm the substituent effects on JAK3 inhibitory activity.
Asunto(s)
Janus Quinasa 3/antagonistas & inhibidores , Piridinas/síntesis química , Piridinas/farmacología , Animales , Proliferación Celular , Inmunomodulación , Linfocitos/efectos de los fármacos , Linfocitos/fisiología , Masculino , Informática Médica , Microsomas Hepáticos/efectos de los fármacos , Microsomas Hepáticos/metabolismo , Modelos Moleculares , Estructura Molecular , Unión Proteica , Piridinas/farmacocinética , Ratas , Ratas Sprague-Dawley , Bazo/citologíaRESUMEN
Small-molecule inhibition of extracellular proteins that activate membrane receptors has proven to be extremely challenging. Diversity-oriented synthesis and small-molecule microarrays enabled the discovery of robotnikinin, a small molecule that binds the extracellular Sonic hedgehog (Shh) protein and blocks Shh signaling in cell lines, human primary keratinocytes and a synthetic model of human skin. Shh pathway activity is rescued by small-molecule agonists of Smoothened, which functions immediately downstream of the Shh receptor Patched.
Asunto(s)
Proteínas Hedgehog/metabolismo , Lactamas/farmacología , Lactonas/farmacología , Transducción de Señal/efectos de los fármacos , Células 3T3 , Animales , Descubrimiento de Drogas , Humanos , Queratinocitos/efectos de los fármacos , Queratinocitos/metabolismo , Lactamas/metabolismo , Lactonas/metabolismo , Ratones , Receptores Patched , Receptores de Superficie Celular/genética , Receptores de Superficie Celular/metabolismoRESUMEN
Palladium(0)-catalyzed reactions of five sets of four stereoisomeric 4,5-epimino-N-(methanesulfonyl) or -N-(arylsulfonyl) 2-enoates reveal that 4,5-cis-(2E)-isomers are thermodynamically more stable than other isomers, in accord with calculations. A highly stereoselective synthesis of (E)-alkene dipeptide isosteres having the desired stereochemistries from unwanted stereoisomeric 4,5-epimino-N-(arylsulfonyl) 2-enoates is also presented.