RESUMEN
The design of a new clinical candidate histamine-H(3) receptor antagonist for the potential treatment of excessive daytime sleepiness (EDS) is described. Phenethyl-R-2-methylpyrrolidine containing biphenylsulfonamide compounds were modified by replacement of the sulfonamide linkage with a sulfone. One compound from this series, 2j (APD916) increased wakefulness in rodents as measured by polysomnography with a duration of effect consistent with its pharmacokinetic properties. The identification of a suitable salt form of 2j allowed it to be selected for further development.
Asunto(s)
Compuestos de Bifenilo/química , Compuestos de Bifenilo/farmacología , Antagonistas de los Receptores Histamínicos/química , Pirrolidinas/química , Pirrolidinas/farmacología , Receptores Histamínicos H3/química , Sulfonas/química , Animales , Área Bajo la Curva , Encéfalo/metabolismo , Sistema Nervioso Central/efectos de los fármacos , Química Farmacéutica/métodos , Diseño de Fármacos , Canal de Potasio ERG1 , Canales de Potasio Éter-A-Go-Go/química , Antagonistas de los Receptores Histamínicos/farmacocinética , Humanos , Concentración 50 Inhibidora , Ratones , Modelos Químicos , Pirrolidinas/antagonistas & inhibidores , Ratas , Sueño/efectos de los fármacos , Temperatura , Vigilia/efectos de los fármacosRESUMEN
Recent developments in sleep research suggest that antagonism of the serotonin 5-HT(2A) receptor may improve sleep maintenance insomnia. We herein report the discovery of a series of potent and selective serotonin 5-HT(2A) receptor antagonists based on a phenethylpiperazine amide core structure. When tested in a rat sleep pharmacology model, these compounds increased both sleep consolidation and deep sleep. Within this series of compounds, an improvement in the metabolic stability of early leads was achieved by introducing a carbonyl group into the phenethylpiperazine linker. Of note, compounds 14 and 27 exhibited potent 5-HT(2A) receptor binding affinity, high selectivity over the 5-HT(2C) receptor, favorable CNS partitioning, and good pharmacokinetic and early safety profiles. In vivo, these two compounds showed dose-dependent, statistically significant improvements on deep sleep (delta power) and sleep consolidation at doses as low as 0.1 mg/kg.
Asunto(s)
Amidas/síntesis química , Piperazinas/síntesis química , Pirazoles/síntesis química , Antagonistas del Receptor de Serotonina 5-HT2 , Trastornos del Inicio y del Mantenimiento del Sueño/tratamiento farmacológico , Sueño/efectos de los fármacos , Administración Oral , Amidas/farmacocinética , Amidas/farmacología , Animales , Disponibilidad Biológica , Proteínas Sanguíneas/metabolismo , Encéfalo/metabolismo , Perros , Agonismo Inverso de Drogas , Haplorrinos , Humanos , Masculino , Microsomas Hepáticos/metabolismo , Piperazinas/farmacocinética , Piperazinas/farmacología , Unión Proteica , Pirazoles/farmacocinética , Pirazoles/farmacología , Ratas , Ratas Sprague-Dawley , Relación Estructura-ActividadRESUMEN
5-Hydroxytryptamine (5-HT)(2A) receptor inverse agonists are promising therapeutic agents for the treatment of sleep maintenance insomnias. Among these agents is nelotanserin, a potent, selective 5-HT(2A) inverse agonist. Both radioligand binding and functional inositol phosphate accumulation assays suggest that nelotanserin has low nanomolar potency on the 5-HT(2A) receptor with at least 30- and 5000-fold selectivity compared with 5-HT(2C) and 5-HT(2B) receptors, respectively. Nelotanserin dosed orally prevented (+/-)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI; 5-HT(2A) agonist)-induced hypolocomotion, increased sleep consolidation, and increased total nonrapid eye movement sleep time and deep sleep, the latter marked by increases in electroencephalogram (EEG) delta power. These effects on rat sleep were maintained after repeated subchronic dosing. In healthy human volunteers, nelotanserin was rapidly absorbed after oral administration and achieved maximum concentrations 1 h later. EEG effects occurred within 2 to 4 h after dosing, and were consistent with vigilance-lowering. A dose response of nelotanserin was assessed in a postnap insomnia model in healthy subjects. All doses (up to 40 mg) of nelotanserin significantly improved measures of sleep consolidation, including decreases in the number of stage shifts, number of awakenings after sleep onset, microarousal index, and number of sleep bouts, concomitant with increases in sleep bout duration. Nelotanserin did not affect total sleep time, or sleep onset latency. Furthermore, subjective pharmacodynamic effects observed the morning after dosing were minimal and had no functional consequences on psychomotor skills or memory. These studies point to an efficacy and safety profile for nelotanserin that might be ideally suited for the treatment of sleep maintenance insomnias.
Asunto(s)
Compuestos de Fenilurea/uso terapéutico , Pirazoles/uso terapéutico , Agonistas del Receptor de Serotonina 5-HT2 , Agonistas de Receptores de Serotonina/uso terapéutico , Trastornos del Inicio y del Mantenimiento del Sueño/tratamiento farmacológico , Sueño/efectos de los fármacos , Adolescente , Adulto , Animales , Línea Celular , Membrana Celular/efectos de los fármacos , Membrana Celular/metabolismo , Relación Dosis-Respuesta a Droga , Método Doble Ciego , Humanos , Ligandos , Masculino , Persona de Mediana Edad , Actividad Motora/efectos de los fármacos , Compuestos de Fenilurea/farmacocinética , Compuestos de Fenilurea/farmacología , Polisomnografía , Unión Proteica , Pirazoles/farmacocinética , Pirazoles/farmacología , Ensayo de Unión Radioligante , Ratas , Ratas Sprague-Dawley , Receptor de Serotonina 5-HT2A/biosíntesis , Proteínas Recombinantes , Agonistas de Receptores de Serotonina/farmacocinética , Agonistas de Receptores de Serotonina/farmacología , Adulto JovenRESUMEN
The current study investigated memory for sequentially presented objects in young rats 6 months old (n = 12) and aged rats 24 months old (n = 12). Rats were tested on a task involving three exploratory trials and one probe test. During the exploratory trials, the rat explored a set of three sequentially presented object pairs (A-A, B-B, and C-C) for 5 min per pair with a 3-min delay between each pair. Following the exploratory trials, a probe test was conducted where the rat was presented simultaneously with one object from the first exploratory trial (A) and one object from the third exploratory trial (C). Results from the exploratory trials showed no significant age-related differences in exploration, indicating that 24-month-old rats explored the object pairs as much as 6-month-old rats. The probe test demonstrated that 6-month-old rats spent significantly more time exploring object A compared to object C, indicating that young rats show intact temporal order memory for the exploratory trial objects. However, 24-month-old rats showed no preference for object A and spent a relatively equal amount of time exploring objects A and C. The results suggest that temporal order memory declines as a result of age-related changes in the rodent brain. The findings also may reflect differences in attraction to objects with different memory strengths. Since age-related differences were not detected during the exploratory trials, age-related differences on the probe trial were not due solely to decreased exploration, motivation, or locomotion.
Asunto(s)
Envejecimiento/fisiología , Reconocimiento en Psicología/fisiología , Percepción Espacial/fisiología , Factores de Edad , Análisis de Varianza , Animales , Atención/fisiología , Conducta Animal/fisiología , Conducta Exploratoria/fisiología , Masculino , Ratas , Ratas Endogámicas F344 , Factores de TiempoRESUMEN
Antagonism of the histamine-H(3) receptor is one tactic being explored to increase wakefulness for the treatment of disorders such as excessive daytime sleepiness (EDS) as well as other sleep or cognitive disorders. Phenethyl-R-2-methylpyrrolidine containing biphenylsulfonamide compounds were shown to be potent and selective antagonists of the H(3) receptor. Several of these compounds demonstrated in vivo activity in a rat model of (R)-alpha-methyl histamine (RAMH) induced dipsogenia, and one compound (4e) provided an increase in wakefulness in rats as measured by polysomnographic methods. However, more detailed analysis of the PK/PD relationship suggested the presence of a common active metabolite which may preclude this series of compounds from further development.
Asunto(s)
Compuestos de Bifenilo/química , Diseño de Fármacos , Agonismo Inverso de Drogas , Antagonistas de los Receptores Histamínicos/química , Antagonistas de los Receptores Histamínicos/farmacología , Receptores Histamínicos H3/metabolismo , Sulfonamidas/química , Sulfonamidas/farmacología , Administración Oral , Animales , Antagonistas de los Receptores Histamínicos/administración & dosificación , Antagonistas de los Receptores Histamínicos/farmacocinética , Humanos , Masculino , Ratas , Ratas Sprague-Dawley , Sulfonamidas/administración & dosificación , Sulfonamidas/farmacocinética , Sed/efectos de los fármacos , Vigilia/efectos de los fármacosRESUMEN
A series of pyrimidine analogues derived from ATC0175 were potent antagonists of human MCH-R1 in vitro. Significantly improved receptor selectivity was achieved with several analogues from this series, but no improvement in brain partitioning was noted. One example from this series was shown to inhibit food intake and decrease body weight in a chronic study. However no clear correlation between the pharmacodynamic effect and the pharmacokinetic data with respect to brain concentration was discernible leading us to conclude that the observed effect was most likely not due to interaction with the MCH-R1.
Asunto(s)
Fármacos Antiobesidad/química , Ciclohexilaminas/química , Pirimidinas/química , Quinazolinas/química , Receptores de Somatostatina/antagonistas & inhibidores , Administración Oral , Animales , Fármacos Antiobesidad/síntesis química , Fármacos Antiobesidad/farmacocinética , Ingestión de Alimentos , Humanos , Masculino , Pirimidinas/síntesis química , Pirimidinas/farmacocinética , Ratas , Ratas Sprague-Dawley , Receptores de Somatostatina/metabolismo , Relación Estructura-Actividad , Pérdida de PesoRESUMEN
GPR119 is a rhodopsin-like GPCR expressed in pancreatic beta-cells and incretin releasing cells in the GI tract. As with incretins, GPR119 increases cAMP levels in these cell types, thus making it a highly attractive potential target for the treatment of diabetes. The discovery of the first reported potent agonist of GPR119, 2-fluoro-4-methanesulfonyl-phenyl)-{6-[4-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-1-yl]-5-nitro-pyrimidin-4-yl}-amine (8g, AR231453), is described starting from an initial inverse agonist screening hit. Compound 8g showed in vivo activity in rodents and was active in an oral glucose tolerance test in mice following oral administration.
Asunto(s)
Hipoglucemiantes/química , Receptores Acoplados a Proteínas G/agonistas , Administración Oral , Animales , Glucemia/efectos de los fármacos , Prueba de Tolerancia a la Glucosa , Humanos , Hipoglucemiantes/síntesis química , Hipoglucemiantes/farmacología , Ratones , Estructura Molecular , Ratas , Relación Estructura-ActividadRESUMEN
A new series of H(3) antagonists derived from the natural product Conessine are presented. Several compounds from these new series retain the potency and selectivity of earlier diamine based analogs while exhibiting improved PK characteristics. One compound (3u) demonstrated functional antagonism of the H(3) receptor in an in vivo pharmacological model.
Asunto(s)
Alcaloides/farmacocinética , Química Farmacéutica/métodos , Antagonistas de los Receptores Histamínicos/farmacología , Receptores Histamínicos H3/química , Animales , Unión Competitiva/efectos de los fármacos , Sistema Nervioso Central/efectos de los fármacos , Diseño de Fármacos , Antagonistas de los Receptores Histamínicos/química , Cinética , Modelos Químicos , Estructura Molecular , Ratas , Relación Estructura-ActividadRESUMEN
A new family of Histamine H(3) receptor antagonists (5a-t) has been prepared based on the structure of the natural product Conessine, a known H(3) antagonist. Several members of the new series are highly potent and selective binders of rat and human H(3) receptors and display inverse agonism at the human H(3) receptor. Compound 5n exhibited promising rat pharmacokinetic properties and demonstrated functional antagonism of the H(3) receptor in an in-vivo pharmacological model.