Asunto(s)
Artritis Juvenil/tratamiento farmacológico , Péptidos y Proteínas de Señalización Intercelular/uso terapéutico , Síndrome de Activación Macrofágica/tratamiento farmacológico , Proteínas Recombinantes/uso terapéutico , Artritis Juvenil/complicaciones , Niño , Humanos , Síndrome de Activación Macrofágica/complicaciones , Masculino , Recurrencia , Resultado del TratamientoRESUMEN
OBJECTIVES: Adult-onset Still's disease (AOSD) is a rare systemic autoinflammatory disease; its management is largely empirical. This is the first clinical study to determine if interleukin (IL)-18 inhibition, using the recombinant human IL-18 binding protein, tadekinig alfa, is a therapeutic option in AOSD. METHODS: In this phase II, open-label study, patients were ≥18 years with active AOSD plus fever or C reactive protein (CRP) levels ≥10 mg/L despite treatment with prednisone and/or conventional synthetic disease-modifying antirheumatic drugs (DMARDs). Previous biological DMARD treatment was permitted. Patients received tadekinig alfa 80 mg or 160 mg subcutaneously three times per week for 12 weeks; those receiving 80 mg not achieving early predicted response criteria (reduction of ≥50% CRP values from baseline and fever resolution) were up-titrated to 160 mg for a further 12 weeks. The primary endpoint was the occurrence of adverse events (AEs) throughout the study. RESULTS: Ten patients were assigned to receive 80 mg tadekinig alfa and 13 patients to the 160 mg dose. One hundred and fifty-five treatment-emerging AEs were recorded, and 47 were considered related to the study drug. Most AEs were mild and resolved after drug discontinuation. Three serious AEs occurred, one possibly related to treatment (toxic optic neuropathy). At week 3, 5 of 10 patients receiving 80 mg and 6 of 12 patients receiving 160 mg achieved the predefined response criteria. CONCLUSIONS: Our results indicate that tadekinig alfa appears to have a favourable safety profile and is associated with early signs of efficacy in patients with AOSD. TRIAL REGISTRATION NUMBER: NCT02398435.
Asunto(s)
Antirreumáticos/administración & dosificación , Péptidos y Proteínas de Señalización Intercelular/administración & dosificación , Enfermedad de Still del Adulto/tratamiento farmacológico , Adulto , Antirreumáticos/efectos adversos , Antirreumáticos/uso terapéutico , Biomarcadores/sangre , Relación Dosis-Respuesta a Droga , Esquema de Medicación , Femenino , Humanos , Inyecciones Subcutáneas , Péptidos y Proteínas de Señalización Intercelular/efectos adversos , Péptidos y Proteínas de Señalización Intercelular/uso terapéutico , Interleucina-18/sangre , Persona de Mediana Edad , Índice de Severidad de la Enfermedad , Enfermedad de Still del Adulto/inmunología , Resultado del Tratamiento , Adulto JovenAsunto(s)
Proteínas Adaptadoras de Señalización CARD/genética , Proteínas de Unión al Calcio/genética , Enterocolitis/genética , Péptidos y Proteínas de Señalización Intercelular/uso terapéutico , Síndrome de Activación Macrofágica/genética , Mutación/genética , Infecciones por Paramyxoviridae/genética , Paramyxoviridae/inmunología , Autoinmunidad/genética , Enterocolitis/diagnóstico , Enterocolitis/terapia , Femenino , Perfilación de la Expresión Génica , Humanos , Lactante , Inflamasomas/genética , Inflamación/genética , Péptidos y Proteínas de Señalización Intercelular/farmacología , Interleucina-18/antagonistas & inhibidores , Síndrome de Activación Macrofágica/diagnóstico , Síndrome de Activación Macrofágica/terapia , Infecciones por Paramyxoviridae/diagnóstico , Infecciones por Paramyxoviridae/terapia , Polimorfismo Genético , Resultado del Tratamiento , Secuenciación del ExomaRESUMEN
During a program directed at selective NK(1) receptor antagonists, we serendipitously discovered an NK(1) receptor ligand with additional affinity for the NK(3) receptor. Recognising an opportunity for a drug discovery program aiming for dual NK(1)/NK(3) receptor antagonists, we prepared a series of analogues from a novel, versatile building block. From this series emerged compounds with high and balanced affinities for the NK(1) and the NK(3) receptors. Typical representatives of this series were active in the gerbil foot tapping assay after oral administration.
Asunto(s)
Antagonistas del Receptor de Neuroquinina-1 , Receptores de Neuroquinina-3/antagonistas & inhibidores , Administración Oral , Animales , Descubrimiento de Drogas , Ligandos , Modelos Moleculares , Receptores de Neuroquinina-1/metabolismo , Receptores de Neuroquinina-3/metabolismoRESUMEN
The discovery of a novel, achiral pyridine class of potent and orally active neurokinin-1 (NK(1)) receptor antagonists is described. The evaluation of this class is briefly outlined, leading to the identification of netupitant 21 and befetupitant 29, two new proprietary chemical entities with high affinity and excellent CNS penetration.
Asunto(s)
Diseño de Fármacos , Antagonistas del Receptor de Neuroquinina-1 , Administración Oral , Aminas/química , Animales , Células CHO , Cricetinae , Reactivos de Enlaces Cruzados/química , Humanos , Estructura Molecular , Piridinas/síntesis química , Piridinas/química , Piridinas/farmacología , Pirimidinas/química , Receptores de Neuroquinina-1/metabolismo , Sensibilidad y Especificidad , Relación Estructura-Actividad , Especificidad por SustratoRESUMEN
RATIONALE: Accumulating evidence suggests a potential role for the 5-HT(6 )receptor in cognitive function and the potential use of 5-HT(6) receptor antagonists in the treatment of learning and memory disorders. OBJECTIVES: The aim of the current study was to investigate the effect of the selective 5-HT(6) receptor antagonist, Ro 04-6790, on both the performance of normal adult rats and restoration of a pharmacological disruption of memory function produced by the non-selective muscarinic receptor antagonist, scopolamine, or the dopamine D(2) receptor antagonist, raclopride, in a rodent model of recognition memory. METHODS: Passive, perceptually based, recognition memory was assessed using a novel object discrimination task. Following habituation to an arena, rats were presented with two identical objects during trial 1 (T(1)) and a novel and familiar object during trial 2 (T(2)). The time spent exploring the two objects in each trial was measured and novel object discrimination assessed in T(2). RESULTS: In the absence of drug all rats spent an equal time exploring the two identical objects in T(1) but more time exploring the novel object in T(2). Scopolamine (but not N-methylscopolamine) and raclopride both produced a dose-dependent reduction in novel object discrimination whilst the 5-HT(6) receptor antagonist, Ro 04-6790, had no effect on discrimination when given alone but completely reversed the scopolamine- but not the raclopride-induced deficit. CONCLUSION: This study demonstrates that acute administration of Ro 04-6790 reverses a cholinergic but not a dopaminergic deficit in a rodent model of recognition memory and provides further support for a role of the 5-HT(6) receptor in the regulation of cognitive function.
Asunto(s)
Conducta Animal/efectos de los fármacos , Antagonistas de Dopamina/farmacología , Memoria/efectos de los fármacos , Antagonistas Muscarínicos/farmacología , Pirimidinas/farmacología , Racloprida/antagonistas & inhibidores , Escopolamina/antagonistas & inhibidores , Antagonistas de la Serotonina/farmacología , Animales , Relación Dosis-Respuesta a Droga , Interacciones Farmacológicas , Masculino , RatasRESUMEN
The combination of a 3,5-bis(trifluoromethyl)phenyl needle with the spiropyrrolo-pyrrole motive as a privileged GPCR scaffold was the basis for designing a focused combinatorial library targeted towards the neurokinin-1 receptor. A solution- and solid-phase method is described and binding affinities of representative compounds are presented.
Asunto(s)
Pirroles/síntesis química , Pirroles/farmacología , Receptores de Neuroquinina-1/metabolismo , Receptores de Neuroquinina-2/metabolismo , Receptores de Neuroquinina-3/metabolismo , Técnicas Químicas Combinatorias , Proteínas de Unión al GTP/metabolismo , Indicadores y Reactivos , Ligandos , Receptores de Neuroquinina-1/efectos de los fármacos , Receptores de Neuroquinina-2/efectos de los fármacos , Receptores de Neuroquinina-3/efectos de los fármacos , Relación Estructura-ActividadRESUMEN
The combination of the 3,5-bis(trifluoromethyl)phenyl group with a spirohydantoin motive as a central scaffold was the basis for the design of a combinatorial library targeted towards the neurokinin-1 receptor. A solution- and solid-phase procedure is described and binding affinities of representative compounds presented.