RESUMEN
A series of 1-Sulfonyl-6-Piperazinyl-7-Azaindoles, showing strong antagonistic activity to 5-HT6 receptor (5-HT6R) was synthesized and characterized. The series was optimized to reduce activity on D2 receptor. Based on the selectivity against this off-target and the analysis of the ADME-tox profile, compound 1c was selected for in vivo efficacy assessment, which demonstrated procognitive effects as shown in reversal of scopolamine induced amnesia in an elevated plus maze test in mice. Compound 3, the demethylated version of compound 1c, was profiled against a panel of 106 receptors, channels and transporters, indicating only D3 receptor as a major off-target. Compound 3 has been selected for this study over compound 1c because of the higher 5-HT6R/D2R binding ratio. These results have defined a new direction for the design of our pseudo-selective 5-HT6R antagonists.
Asunto(s)
Amnesia/tratamiento farmacológico , Indoles/farmacología , Piperazinas/farmacología , Receptores de Serotonina/metabolismo , Antagonistas de la Serotonina/farmacología , Sulfonas/farmacología , Amnesia/inducido químicamente , Animales , Conducta Animal/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Humanos , Indoles/síntesis química , Indoles/química , Aprendizaje por Laberinto/efectos de los fármacos , Ratones , Modelos Moleculares , Estructura Molecular , Piperazinas/síntesis química , Piperazinas/química , Escopolamina , Antagonistas de la Serotonina/síntesis química , Antagonistas de la Serotonina/química , Relación Estructura-Actividad , Sulfonas/síntesis química , Sulfonas/químicaRESUMEN
The design, synthesis, and structure-activity relationships of a novel series of pyrazines, acting as corticotropin releasing factor-1 (CRF-1) receptor antagonists, are described. Synthetic methodologies were developed to prepare a number of substituted pyrazine cores utilizing regioselective halogenation and chemoselective derivatization. Noteworthy, an efficient 5-step synthesis was developed for the lead compound 59 (NGD 98-2), which required no chromatography. Compound 59 was characterized as an orally bioavailable, brain penetrant, and highly selective CRF-1 receptor antagonist. Occupancy of rat brain CRF-1 receptors was quantified using ex vivo receptor occupancy assays, using both brain tissue homogenates as well as brain slices receptor autoradiography. Behaviorally, oral administration of 59 significantly antagonized CRF-induced locomotor activity at doses as low as 10 mg/kg and dose-dependently reduced the restraint stress-induced ACTH increases.
Asunto(s)
Pirazinas/síntesis química , Receptores de Hormona Liberadora de Corticotropina/antagonistas & inhibidores , Tejido Adiposo/metabolismo , Administración Oral , Hormona Adrenocorticotrópica/sangre , Animales , Disponibilidad Biológica , Barrera Hematoencefálica/metabolismo , Línea Celular , Corteza Cerebral/metabolismo , Humanos , Técnicas In Vitro , Inyecciones Intraventriculares , Masculino , Microsomas Hepáticos/metabolismo , Actividad Motora/efectos de los fármacos , Pirazinas/química , Pirazinas/farmacología , Ensayo de Unión Radioligante , Ratas , Receptores de Hormona Liberadora de Corticotropina/metabolismo , Restricción Física , Relación Estructura-ActividadRESUMEN
The design, synthesis and structure-activity relationship studies of a novel series of CRF-1 receptor antagonists, the 2-arylpyrimidines, are described. The effects of substitution on the aromatic ring and the pyrimidine core on CRF-1 receptor binding were investigated. A number of compounds with K(i) values below 10 nM and lipophilicity in a minimally acceptable range for a CNS drug (cLogP<5) were discovered.
Asunto(s)
Química Farmacéutica/métodos , Pirimidinas/química , Pirimidinas/síntesis química , Receptores de Hormona Liberadora de Corticotropina/antagonistas & inhibidores , Animales , Sitios de Unión , Química Farmacéutica/instrumentación , Diseño de Fármacos , Humanos , Cinética , Modelos Químicos , Conformación Molecular , Estructura Molecular , Ratas , Ratas Sprague-Dawley , Solubilidad , Relación Estructura-ActividadRESUMEN
The design, synthesis and structure-activity relationships of a novel series of CRF-1 receptor antagonist, the 1-aryl-4-alkylaminoisoquinolines, is described. The effects of substitution on the aromatic ring, the amino group and the isoquinoline core on CRF-1 receptor binding were investigated.