RESUMEN
A potent IRAK-4 inhibitor was identified through routine project cross screening. The binding mode was inferred using a combination of in silico docking into an IRAK-4 homology model, surrogate crystal structure analysis and chemical analogue SAR.
Asunto(s)
Diseño de Fármacos , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/farmacología , Imidazoles/síntesis química , Imidazoles/farmacología , Quinasas Asociadas a Receptores de Interleucina-1/antagonistas & inhibidores , Modelos Moleculares , Piridinas/síntesis química , Piridinas/farmacología , Sitios de Unión , Cristalografía por Rayos X , Inhibidores Enzimáticos/química , Imidazoles/química , Conformación Molecular , Estructura Molecular , Piridinas/química , Relación Estructura-ActividadRESUMEN
Following the identification of a potent IRAK inhibitor through routine project cross screening, a novel class of IRAK-4 inhibitor was established. The SAR of imidazo[1,2-a]pyridino-pyridines and benzimidazolo-pyridines was explored.
Asunto(s)
Quinasas Asociadas a Receptores de Interleucina-1/antagonistas & inhibidores , Inhibidores de Proteínas Quinasas/farmacología , Piridinas/farmacología , Evaluación Preclínica de Medicamentos , Estructura Molecular , Inhibidores de Proteínas Quinasas/síntesis química , Inhibidores de Proteínas Quinasas/química , Piridinas/síntesis química , Piridinas/química , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
The synthesis and profile of a series of amides are described. Some of these compounds were potent IRAK-4 inhibitors and two examples were evaluated in vivo.
Asunto(s)
Amidas/síntesis química , Amidas/farmacología , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/farmacología , Quinasas Asociadas a Receptores de Interleucina-1/antagonistas & inhibidores , Modelos Biológicos , Piridinas/síntesis química , Piridinas/farmacología , Bibliotecas de Moléculas Pequeñas/síntesis química , Bibliotecas de Moléculas Pequeñas/farmacología , Amidas/química , Diseño de Fármacos , Inhibidores Enzimáticos/química , Humanos , Estructura Molecular , Piridinas/química , Bibliotecas de Moléculas Pequeñas/química , Relación Estructura-ActividadRESUMEN
Menthol has historically been used topically to alleviate various pain conditions. At low concentrations, this non-selective TRPM8 agonist elicits a cooling sensation, however higher concentrations result in cold hyperalgesia in normal subjects and paradoxically analgesia in neuropathic patients. Through behavioural and electrophysiological means, we examined whether this back-translated into a pre-clinical rodent model. Menthol was applied topically to the hind paws of naive and spinal nerve-ligated (SNL) rats. In behavioural assays, menthol did not affect withdrawal thresholds to mechanical stimulation and 10% and 40% menthol rarely sensitised withdrawals to innocuous cooling in naïve rats. However, in SNL rats, 10% and 40% menthol alleviated cold hypersensitivity. This was partly corroborated by in vivo electrophysiological recordings of dorsal horn lamina V/VI neurones. As several studies have implicated TRPM8 in analgesia, we examined whether a novel systemically available TRPM8 agonist, M8-Ag, had more potent anti-hyperalgesic effects than menthol in neuropathic rats. In vitro, M8-Ag activates TRPM8, expressed in HEK293 cells, with an EC50 of 44.97 nM. In vivo, M8-Ag inhibited neuronal responses to innocuous and noxious cooling in SNL rats with no effect in sham-operated rats. This effect was modality selective; M8-Ag did not alter neuronal responses to mechanical, heat or brush stimulation. In addition, M8-Ag attenuated behavioural hypersensitivity to innocuous cooling but not mechanical stimulation. These data suggest that menthol induced hyperalgesia is not consistently replicable in the rat and that the analgesic properties are revealed by injury. Systemic TRPM8 agonists might be beneficial in neuropathy without affecting normal cold sensitivity.
Asunto(s)
Analgésicos/uso terapéutico , Hiperalgesia/tratamiento farmacológico , Mentol/uso terapéutico , Morfolinas/agonistas , Neuralgia/tratamiento farmacológico , Canales Catiónicos TRPM/agonistas , Triazoles/agonistas , Analgésicos/administración & dosificación , Animales , Frío , Modelos Animales de Enfermedad , Hiperalgesia/etiología , Masculino , Mentol/administración & dosificación , Neuralgia/etiología , Umbral del Dolor/efectos de los fármacos , Traumatismos de los Nervios Periféricos/complicaciones , Ratas , Ratas Sprague-DawleyRESUMEN
The synthesis of a series of novel C-linked nucleotide triphosphates is reported. These exhibit excellent agonist potency and selectivity for the P2Y2 receptor with a number of examples having EC50 values below 10 nM. Representative compounds from the N-linked and C-linked series showed enhanced metabolic stability compared with that of the natural ligand UTP.
Asunto(s)
Nucleótidos/síntesis química , Nucleótidos/farmacología , Agonistas del Receptor Purinérgico P2 , Uridina Trifosfato/química , Línea Celular Tumoral , Cromatografía Liquida , Humanos , Indicadores y Reactivos , Ligandos , Espectroscopía de Resonancia Magnética , Espectrometría de Masas , Nucleótidos/química , Receptores Purinérgicos P2Y2 , Proteínas Recombinantes , Espectrofotometría Ultravioleta , Uridina Trifosfato/farmacologíaRESUMEN
The synthesis and P2Y2 activities of a novel series of nucleoside triphosphates are described. Many of these compounds were potent agonists of the P2Y2 receptor.
Asunto(s)
Nucleótidos/síntesis química , Nucleótidos/farmacología , Agonistas del Receptor Purinérgico P2 , Línea Celular Tumoral , ADN Complementario/biosíntesis , ADN Complementario/genética , Humanos , Indicadores y Reactivos , Espectroscopía de Resonancia Magnética , Receptores Purinérgicos P2Y2 , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Relación Estructura-Actividad , Uridina Trifosfato/farmacologíaRESUMEN
The study of non-oxazole containing indole fragments as inhibitors of inosine monophosphate dehydrogenase (IMPDH) is described. The synthesis and in vitro inhibitory values for IMPDH II are discussed.
Asunto(s)
Inhibidores Enzimáticos/farmacología , IMP Deshidrogenasa/antagonistas & inhibidores , Indoles/farmacología , Carbamatos/química , Carbamatos/farmacología , Cristalografía por Rayos X , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/química , Enlace de Hidrógeno , Indoles/síntesis química , Indoles/química , Modelos Moleculares , Estructura Molecular , Peso Molecular , Oxazoles/farmacología , Compuestos de Fenilurea/química , Compuestos de Fenilurea/farmacología , Sensibilidad y Especificidad , Relación Estructura-ActividadRESUMEN
The elaboration of previously reported indole fragments as inhibitors of inosine monophosphate dehydrogenase (IMPDH) is described. The synthesis, in vitro inhibitory values for IMPDH II, PBMC proliferation and physicochemical properties are discussed.