RESUMEN
A novel molecular scaffold, dihydropyridothienopyrimidin-4,9-dione, was synthesized from benzylamine or p-methoxybenzylamine in six steps involving successive ring closure to form a fused ring system composed of dihydropyridone, thiophene and pyrimidone. The pharmacological versatility of the dihydropyridothenopyrimidin-4,9-dione scaffold was demonstrated by inhibitory activity against metabotropic glutamate receptor subtype 1 (mGluR1), which shows that the title compounds can serve as an interesting scaffold for the discovery of potential bioactive molecules for the treatment of human diseases.
Asunto(s)
Pirimidinas/síntesis química , Receptores de Glutamato Metabotrópico/antagonistas & inhibidores , Bencilaminas/química , Humanos , Estructura Molecular , Pirimidinas/química , Pirimidinas/farmacologíaRESUMEN
A series of 2-amino and 2-methoxy quinoline-6-carboxamide derivatives have been synthesized and their metabotropic glutamate receptor type 1 (mGluR1) antagonistic activities were evaluated in a functional cell-based assay. The compound 13c showed the highest potency with IC50 value of 2.16 µM against mGluR1. Finally, in vivo evaluation of 13c in the rat spinal nerve ligation (SNL) model exhibited weak analgesic effects with regard to both mechanical allodynia and cold allodynia.
Asunto(s)
Neuralgia/tratamiento farmacológico , Piperidinas/farmacología , Quinolinas/farmacología , Receptores de Glutamato Metabotrópico/antagonistas & inhibidores , Animales , Frío , Relación Dosis-Respuesta a Droga , Canales de Potasio Éter-A-Go-Go/antagonistas & inhibidores , Humanos , Hiperalgesia/tratamiento farmacológico , Ratones , Estructura Molecular , Dimensión del Dolor/efectos de los fármacos , Piperidinas/síntesis química , Piperidinas/química , Quinolinas/síntesis química , Quinolinas/química , Ratas , Relación Estructura-ActividadRESUMEN
We described here the synthesis and biological evaluation of mGluR5 antagonists containing a quinoline ring structure. Using intracellular calcium mobilization assay (FDSS assay), we identified compound 5n, showing high inhibitory activity against mGluR5. In addition, it was found that compound 5n has excellent stability profile. Finally, this compound exhibited favorable analgesic effects in spinal nerve ligation model of neuropathic pain, which is comparable to gabapentin.
Asunto(s)
Acetileno/análogos & derivados , Neuralgia/tratamiento farmacológico , Quinolinas/síntesis química , Quinolinas/farmacología , Receptor del Glutamato Metabotropico 5/antagonistas & inhibidores , Acetileno/química , Acetileno/farmacología , Células HEK293 , Humanos , Quinolinas/químicaRESUMEN
Agonists of the 5-HT(2C) receptor have attracted much attention as therapeutic agents for the treatment of obesity. Subtype selectivity against other 5-HT(2) receptors is one of the most important prerequisites for reducing side effects. We present the synthesis of N-methyl-N-(1-methylpiperidin-4-yl)benzenesulfonamide analogs and their structure-activity relationship studies on 5-HT(2A) and 5-HT(2C) receptors. Although the compounds showed nanomolar activity to the 5-HT(2C) receptor, their selectivity against the 5-HT(2A) receptor was modest to low. Molecular modeling studies using homology modeling and docking simulation revealed that selectivity originated from subtype specific residues. The observed binding modes and receptor-ligand interactions provided us a clue for optimizing the selectivity against the 5-HT(2A) receptor.
Asunto(s)
Piperidinas/síntesis química , Receptor de Serotonina 5-HT2C/química , Sulfonamidas/síntesis química , Secuencia de Aminoácidos , Simulación por Computador , Diseño de Fármacos , Humanos , Concentración 50 Inhibidora , Ligandos , Modelos Químicos , Modelos Moleculares , Conformación Molecular , Datos de Secuencia Molecular , Piperidinas/farmacología , Unión Proteica , Receptor de Serotonina 5-HT2C/metabolismo , Homología de Secuencia de Aminoácido , Serotonina/metabolismo , Relación Estructura-Actividad , Sulfonamidas/farmacología , BencenosulfonamidasRESUMEN
We have developed a facile synthesis of 3,3-diphenylpropanamides using Meldrum's acid derivatives as amide coupling components. The in vitro biological evaluation of the title compounds led to the identification of compound 1h, which has good inhibitory activity against T-type calcium channel (IC(50) = 0.83 µM).
Asunto(s)
Compuestos de Bencidrilo/síntesis química , Bloqueadores de los Canales de Calcio/síntesis química , Canales de Calcio Tipo T/química , Piperazinas/química , Compuestos de Bencidrilo/química , Compuestos de Bencidrilo/farmacología , Bloqueadores de los Canales de Calcio/química , Bloqueadores de los Canales de Calcio/farmacología , Canales de Calcio Tipo T/metabolismo , Canal de Potasio ERG1 , Canales de Potasio Éter-A-Go-Go/antagonistas & inhibidores , Canales de Potasio Éter-A-Go-Go/metabolismo , Ensayos Analíticos de Alto Rendimiento , Humanos , Piperazinas/síntesis química , Piperazinas/farmacología , Relación Estructura-ActividadRESUMEN
A serine-threonine kinase IKK-2 plays an important role in activation of NF-κB through phosphorylation of the inhibitor of NF-κB (IκB). As NF-κB is a major transcription factor that regulates genes responsible for cell proliferation and inflammation, development of selective IKK-2 inhibitors has been an important area of anti-inflammatory and anti-cancer research. In this study, to obtain active and selective IKK-2 inhibitors, various substituents were introduced to a piperidinyl aminopyrimidine core structure. The structure-activity relationship study indicated that hydrogen, methanesulfonyl, and aminosulfonyl groups substituted at the piperidinylamino functionality provide high inhibitory activity against IKK-2. Also, morpholinosulfonyl and piperazinosulfonyl group substituted at the aromatic ring attached to the aminopyrimidine core significantly increased the inhibitory activity of the resulting derivatives. In particular, compound 17 with the aromatic piperazinosulfonyl substituent showed the most potent (IC(50)=1.30 µM) and selective (over other kinases such as p38α, p38ß, JNK1, JNK2, JNK3, and IKK-1) inhibitory activity against IKK-2.
Asunto(s)
Descubrimiento de Drogas , Activación Enzimática/efectos de los fármacos , Inhibidores Enzimáticos/farmacología , Quinasa I-kappa B/antagonistas & inhibidores , Piperidinas/química , Pirimidinas/farmacología , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/química , Humanos , Concentración 50 Inhibidora , Estructura Molecular , Pirimidinas/síntesis química , Pirimidinas/química , Relación Estructura-ActividadRESUMEN
The aim of this study was to investigate the relationship between hepatotoxicity, levels of glucuronide conjugates of valproic acid (VPA), and the toxic metabolites of VPA (4-ene VPA and 2,4-diene VPA). We also examined whether hepatotoxicity could be predicted by the urinary excretion levels of VPA and its toxic metabolites. VPA was administrated orally in rats in amounts ranging from 20 mg/kg to 500 mg/kg. Free and total (free plus glucuronide conjugated) VPA, 4-ene VPA, and 2,4-diene VPA were quantified in urine and liver using gas chromatography-mass spectrometry. Serum levels of aspartate aminotransferase, alanine aminotransferase, and alpha-glutathione S-transferase (alpha-GST) were also determined to measure the level of hepatotoxicity. The serum alpha-GST level increased slightly at the 20 mg/kg dose, and substantially increased at the 100 and 500 mg/kg dose; aspartate aminotransferase and alanine aminotransferase levels did not change with the administration of increasing doses of VPA. The liver concentration of free 4-ene VPA and the urinary excretion of total 4-ene VPA were the only measures that correlated with the increase in the serum alpha-GST level (p < 0.094 and p < 0.023 respectively). From these results, we conclude that hepatotoxicity of VPA correlates with liver concentration of 4-ene VPA and can be predicted by the urinary excretion of total 4-ene VPA.
Asunto(s)
Anticonvulsivantes/farmacocinética , Anticonvulsivantes/toxicidad , Enfermedad Hepática Inducida por Sustancias y Drogas , Hígado/efectos de los fármacos , Ácido Valproico/farmacocinética , Ácido Valproico/toxicidad , Administración Oral , Alanina Transaminasa/sangre , Animales , Anticonvulsivantes/administración & dosificación , Anticonvulsivantes/orina , Aspartato Aminotransferasas/sangre , Biotransformación , Relación Dosis-Respuesta a Droga , Ácidos Grasos Monoinsaturados/farmacocinética , Ácidos Grasos Monoinsaturados/toxicidad , Cromatografía de Gases y Espectrometría de Masas , Glutatión Transferasa/sangre , Isoenzimas/sangre , Hígado/metabolismo , Hepatopatías/metabolismo , Masculino , Ratas , Ratas Sprague-Dawley , Ácido Valproico/administración & dosificación , Ácido Valproico/análogos & derivados , Ácido Valproico/orinaRESUMEN
5-HT(7) receptor antagonists generated antidepressant-like effects in animal model and the involvement of the 5-HT(7) receptor in other pathophysiological mechanisms such as thermoregulation, learning and memory, and sleep has been highlighted by various studies. As one of our efforts to discover a new type of 5-HT(7) receptor antagonists, we here report on the synthesis and binding affinities to the 5-HT(7) receptor of the quinazolinone library 1, which was designed with various substituents (X, Y, R(1), and R(2)) on the aromatic rings and different carbon chain length. Total 85 compounds of the quinazolinone library 1 were synthesized and the binding affinities of all the synthesized compounds were obtained by radioligand binding assay for the 5-HT(7) receptor. Among the 85 compounds, 24 compounds show very good binding affinities with IC(50) values below 100 nM. Mainly the compounds with IC(50) values below 100 nM have o-OMe or o-OEt as R(2) substituent. The compound with the best binding affinity is 1-68 of which the IC(50) value is 12 nM. In in vivo animal study, some synthesized compounds really have the antidepressant activity in the forced swimming test in mice.
Asunto(s)
Quinazolinonas/síntesis química , Receptores de Serotonina/química , Receptores de Serotonina/metabolismo , Animales , Antidepresivos/síntesis química , Antidepresivos/química , Antidepresivos/uso terapéutico , Depresión/tratamiento farmacológico , Ligandos , Ratones , Estructura Molecular , Neurotransmisores/síntesis química , Neurotransmisores/química , Quinazolinonas/química , Quinazolinonas/uso terapéutico , Antagonistas de la Serotonina/síntesis química , Antagonistas de la Serotonina/química , Antagonistas de la Serotonina/farmacología , Relación Estructura-Actividad , NataciónRESUMEN
Metabotropic glutamate receptor 1 (mGluR1) has been a prime target for drug discovery due to its heavy involvement in various brain disorders. Recent studies suggested that mGluR1 is associated with chronic pain and can serve as a promising target for the treatment of neuropathic pain. In an effort to develop a novel mGluR1 antagonist, we designed and synthesized a library of compounds with tetrahydrothieno[2,3-c]pyridine scaffold. Among these compounds, compound 9b and 10b showed excellent antagonistic activity in vitro and demonstrated pain-suppressing activity in animal models of pain. Both compounds were orally active, and compound 9b exhibited a favorable pharmacokinetic profile in rats. We believe that these compounds can provide a promising lead compound that is suitable for the potential treatment of neuropathic pain.