RESUMEN
Melanin-concentrating hormone (MCH) is a cyclic, nonadecapeptide expressed in the CNS of all vertebrates that regulates feeding behavior and energy homeostasis via interaction with the central melanocortin system. Regulation of this interaction results in modulation of food intake and body weight gain, demonstrating significant therapeutic potential for the treatment of obesity. The MCH-1 receptor (MCH-R1) has been identified as a key target in MCH regulation, as small molecule antagonists of MCH-R1 have demonstrated activity in vivo. Herein, we document our research in a bicyclo[3.1.0]hexyl urea series with particular emphasis on structure-activity relationships and optimization of receptor occupancy, measured both in vitro and via an ex vivo binding assay following an oral dosing regimen. Several compounds have been tested in vivo and exhibit oral efficacy in relevant acute rodent feeding models. In particular, 24u has proven efficacious in chronic rodent models of obesity, showing a statistically significant reduction in food intake and body weight over a 28 day study.
Asunto(s)
Fármacos Antiobesidad/síntesis química , Compuestos de Fenilurea/síntesis química , Piperazinas/síntesis química , Receptores de Somatostatina/antagonistas & inhibidores , Urea/análogos & derivados , Urea/síntesis química , Administración Oral , Animales , Fármacos Antiobesidad/farmacología , Disponibilidad Biológica , Peso Corporal/efectos de los fármacos , Encéfalo/metabolismo , Células CHO , Cricetinae , Cricetulus , Ingestión de Alimentos/efectos de los fármacos , Semivida , Masculino , Obesidad/tratamiento farmacológico , Compuestos de Fenilurea/farmacología , Piperazinas/farmacología , Ensayo de Unión Radioligante , Ratas , Receptores de Somatostatina/metabolismo , Relación Estructura-Actividad , Distribución Tisular , Urea/farmacologíaRESUMEN
Melanin concentrating hormone (MCH) is a cyclic neuropeptide expressed in the lateral hypothalamus that plays an important role in energy homeostasis. To investigate the pharmacological consequences of inhibiting MCH signaling in murine obesity models, we examined the effect of acute and chronic administration of a selective MCH1 receptor antagonist (SCH-A) in diet-induced obese (DIO) and Lep(ob/ob) mice. Oral administration of SCH-A for 5 consecutive days (30 mg/kg q.d.) produced hypophagia, a loss of body weight and adiposity, and decreased plasma leptin levels in DIO mice, and hypophagia and reduced weight gain in Lep(ob/ob) mice. Chronic administration of SCH-A to DIO mice decreased food intake, body weight and adiposity, and plasma leptin and free fatty acids. These effects were accompanied by increases in several hypothalamic neuropeptides. Acute administration of SCH-A (30 mg/kg) prevented the decrease in energy expenditure associated with food restriction. These results indicate that MCH1 receptor antagonists may be effective in the treatment of obesity.
Asunto(s)
Ingestión de Alimentos/efectos de los fármacos , Metabolismo Energético/efectos de los fármacos , Nitrilos/farmacología , Obesidad/fisiopatología , Piperazinas/farmacología , Receptores de Somatostatina/antagonistas & inhibidores , Urea/análogos & derivados , Tejido Adiposo/efectos de los fármacos , Administración Oral , Animales , Unión Competitiva , Peso Corporal/efectos de los fármacos , Encéfalo/metabolismo , Células CHO , Cricetinae , Cricetulus , Grasas de la Dieta/administración & dosificación , Relación Dosis-Respuesta a Droga , Ácidos Grasos no Esterificados/sangre , Femenino , Galanina/genética , Expresión Génica/efectos de los fármacos , Homeostasis/efectos de los fármacos , Hormonas Hipotalámicas/genética , Hipotálamo/efectos de los fármacos , Hipotálamo/metabolismo , Insulina/sangre , Péptidos y Proteínas de Señalización Intracelular/genética , Radioisótopos de Yodo , Leptina/sangre , Masculino , Melaninas/genética , Ratones , Ratones Endogámicos C57BL , Ratones Obesos , Neuropéptido Y/genética , Neuropéptidos/genética , Nitrilos/administración & dosificación , Obesidad/etiología , Oligopéptidos/metabolismo , Receptores de Orexina , Orexinas , Piperazinas/administración & dosificación , Hormonas Hipofisarias/genética , Unión Proteica , Receptores Acoplados a Proteínas G , Receptores de Neuropéptido , Receptores de Somatostatina/genética , Receptores de Somatostatina/metabolismo , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Triglicéridos/sangre , Urea/administración & dosificación , Urea/farmacologíaRESUMEN
Melanin concentrating hormone (MCH) is involved in regulation of food intake and energy homeostasis. Antagonists of the MCH receptor are expected to affect food intake and weight gain, making MCH-R1 an attractive target for obesity treatment. Herein, we report the discovery of a novel, orally active series of MCH-R1 antagonists that exhibit in vivo efficacy in rodent obesity models.
Asunto(s)
Fármacos Antiobesidad/síntesis química , Compuestos Bicíclicos con Puentes/síntesis química , Receptores de la Hormona Hipofisaria/antagonistas & inhibidores , Receptores de Somatostatina/antagonistas & inhibidores , Urea/análogos & derivados , Urea/síntesis química , Administración Oral , Animales , Fármacos Antiobesidad/química , Fármacos Antiobesidad/farmacología , Disponibilidad Biológica , Encéfalo/metabolismo , Compuestos Bicíclicos con Puentes/química , Compuestos Bicíclicos con Puentes/farmacología , Cicloheptanos/síntesis química , Cicloheptanos/química , Cicloheptanos/farmacología , Ciclohexanos/síntesis química , Ciclohexanos/química , Ciclohexanos/farmacología , Ingestión de Alimentos/efectos de los fármacos , Ratones , Obesidad/tratamiento farmacológico , Ratas , Urea/química , Urea/farmacologíaRESUMEN
The development of a novel series of tetrahydroquinoline-derived gamma-secretase inhibitors for the potential treatment of Alzheimer's disease is described.
Asunto(s)
Enfermedad de Alzheimer/tratamiento farmacológico , Secretasas de la Proteína Precursora del Amiloide/antagonistas & inhibidores , Inhibidores de Proteasas/química , Quinolinas/química , Sulfonamidas/química , Humanos , Inhibidores de Proteasas/síntesis química , Quinolinas/síntesis química , Relación Estructura-Actividad , Sulfonamidas/síntesis químicaRESUMEN
A novel piperidine series of gamma-secretase inhibitors, potentially useful for the treatment of Alzheimer's disease, is disclosed. SAR investigation revealed the requirement for cis-stereochemistry of the substituents attached to the core, which resulted in the chair-like diaxial conformation of the piperidine ring. The series was optimized to provide inhibitors with IC(50)'s in the single-digit nanomolar range. Absolute stereochemistry of the active enantiomer was assigned.
Asunto(s)
Enfermedad de Alzheimer/tratamiento farmacológico , Secretasas de la Proteína Precursora del Amiloide/antagonistas & inhibidores , Piperidinas/química , Inhibidores de Proteasas/química , Concentración 50 Inhibidora , Piperidinas/síntesis química , Inhibidores de Proteasas/síntesis química , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
Herein, we report the discovery of an effective strategy to modulate liabilities related to affinity of previously disclosed bicyclohexane MCHR-1 antagonists for the hERG channel. This paper describes one of several strategies incorporated to limit hERG binding via modifications of a terminal aryl group in an otherwise promising bicyclohexyl urea series.
Asunto(s)
Canales de Potasio Éter-A-Go-Go/metabolismo , Melaninas/química , Receptores de Somatostatina/antagonistas & inhibidores , Urea/farmacología , Química Farmacéutica , Diseño de Fármacos , Humanos , Concentración 50 Inhibidora , Cinética , Modelos Químicos , Unión Proteica , Urea/químicaRESUMEN
Melanin concentrating hormone (MCH) receptor antagonists have been proposed as potential treatments of obesity. MCH receptor antagonists with a biphenylamine subunit have been reported previously at Schering-Plough. Herein, we report the discovery of bicyclo[4.1.0]heptanes as replacements for the middle phenyl ring of the biphenylamine moiety in order to eliminate its potential mutagenic liability. Structure-activity relationships in this series were found to be very similar to those of the original biphenylamine series, suggesting that the two series have similar binding modes.
Asunto(s)
Compuestos de Aminobifenilo/química , Compuestos Bicíclicos con Puentes/química , Heptanos/química , Receptores de la Hormona Hipofisaria/antagonistas & inhibidores , Animales , Línea Celular , Cricetinae , Evaluación Preclínica de Medicamentos , Heptanos/farmacología , Ratones , Estructura Molecular , Mutágenos/química , Ratas , Relación Estructura-ActividadRESUMEN
In search of a PDE5 inhibitor for erectile dysfunction, an SAR was developed from a PDE1/PDE5 purine series of leads, which had modest PDE5 potency and poor isozyme selectivity. A compound (41) with PDE5 inhibition and in vivo activity similar to sildenafil was discovered from this effort. In addition, purine 41 demonstrated superior overall PDE isozyme selectivity when compared to the approved PDE5 inhibitors sildenafil, vardenafil, and tadalafil, which may result in a more favorable side-effect profile.
Asunto(s)
Disfunción Eréctil/tratamiento farmacológico , Fosfodiesterasa I/metabolismo , Inhibidores de Fosfodiesterasa/síntesis química , Inhibidores de Fosfodiesterasa/uso terapéutico , Hidrolasas Diéster Fosfóricas/metabolismo , Purinas/síntesis química , Purinas/uso terapéutico , 3',5'-GMP Cíclico Fosfodiesterasas , Animales , Fosfodiesterasas de Nucleótidos Cíclicos Tipo 5 , Humanos , Masculino , Modelos Moleculares , Estructura Molecular , Piperazinas/farmacología , Purinas/química , Ratas , Citrato de Sildenafil , Relación Estructura-Actividad , Sulfonas , Vasodilatadores/síntesis química , Vasodilatadores/farmacología , Vasodilatadores/uso terapéuticoRESUMEN
The four 2,2,5-regioisomer counterparts of SCH 51048 were synthesized and evaluated. As with the parent series, only the two cis isomers possessed any in vitro activity, and only the activity of the isomer with the R-configuration at the tetrahydrofuran 2-carbon was significant. The activity data suggests that oxygen at only one of the two possible ring positions benzylic to the difluorobenzene participates usefully in active site binding.