RESUMEN
AG-045572 (CMPD1, 1 a) is a nonpeptidic gonadotropin-releasing hormone (GnRH) antagonist that has been investigated for the treatment of sex hormone-related diseases. In the context of systematic studies on sila-substituted drugs, the silicon analogue disila-AG-045572 (1 b) and its derivative 2 were prepared in multi-step syntheses and characterized by elemental analyses (C, H, N), NMR spectroscopic studies (1H, 13C, 29Si), and single-crystal X-ray diffraction. The pharmacological properties of compounds 1 a, 1 b, and 2 were compared in terms of their in vitro potency at cloned human and rat GnRH receptors. Compounds 1 a and 2 were also examined in regard to their pharmacokinetics and in vivo efficacy in both castrated rat (luteinizing hormone (LH) suppression) and intact rat (testosterone suppression) models. The efficacy and pharmacokinetic profiles of 1 a and its silicon-containing analogue 2 appear similar, indicating that replacement of the 5,6,7,8-tetrahydronaphthalene ring system by the 1,3-disilaindane skeleton led to retention of efficacy. Therefore, the silicon compound 2 represents a novel drug prototype for the design of potent, orally available GnRH antagonists suitable for once-daily dosing.
Asunto(s)
Furanos/química , Hormona Liberadora de Gonadotropina/antagonistas & inhibidores , Antagonistas de Hormonas/química , Antagonistas de Hormonas/farmacología , Tetrahidronaftalenos/química , Animales , Cristalografía por Rayos X , Evaluación Preclínica de Medicamentos , Furanos/farmacología , Antagonistas de Hormonas/farmacocinética , Humanos , Hormona Luteinizante/antagonistas & inhibidores , Espectroscopía de Resonancia Magnética , Masculino , Estructura Molecular , Orquiectomía , Ratas Wistar , Receptores LHRH/genética , Silicio/química , Relación Estructura-Actividad , Tetrahidronaftalenos/farmacologíaRESUMEN
The synthesis, physicochemical properties and pharmacological profiles of two novel silicon-containing p38 MAP kinase inhibitors are described.
Asunto(s)
Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/farmacología , Pirazoles/síntesis química , Pirazoles/farmacología , Compuestos de Silicona/química , Proteínas Quinasas p38 Activadas por Mitógenos/antagonistas & inhibidores , Animales , Fenómenos Químicos , Química Farmacéutica , Química Física , Cristalografía por Rayos X , Inhibidores Enzimáticos/farmacocinética , Humanos , Técnicas In Vitro , Indicadores y Reactivos , Lipopolisacáridos/farmacología , Ratones , Microsomas Hepáticos/enzimología , Microsomas Hepáticos/metabolismo , Modelos Moleculares , Estereoisomerismo , Factor de Necrosis Tumoral alfa/metabolismoRESUMEN
Sila-substitution of drugs (the carbon/silicon switch) is a concept that is being successfully used for the development of new chemical entities. The (R)-sila-analogue of the antidepressant venlafaxine is devoid of the serotonin reuptake inhibition observed with the marketed drug, leading to a selective noradrenaline reuptake inhibitor displaying anti-emetic properties.
Asunto(s)
Antieméticos/farmacología , Antieméticos/uso terapéutico , Inhibidores Selectivos de la Recaptación de Serotonina/farmacología , Inhibidores Selectivos de la Recaptación de Serotonina/uso terapéutico , Vómitos/tratamiento farmacológico , Animales , Antieméticos/síntesis química , Cristalografía por Rayos X , Ciclohexanoles/química , Ciclohexanoles/farmacología , Ciclohexanoles/uso terapéutico , Modelos Animales de Enfermedad , Evaluación Preclínica de Medicamentos , Hurones , Humanos , Técnicas In Vitro , Masculino , Modelos Moleculares , Estructura Molecular , Antagonistas del Receptor de Serotonina 5-HT3 , Inhibidores Selectivos de la Recaptación de Serotonina/síntesis química , Estereoisomerismo , Relación Estructura-Actividad , Clorhidrato de VenlafaxinaRESUMEN
A series of bicyclic heteroaryl ring systems was considered as a replacement for the 3-cyclopentyloxy-4-methoxyphenyl moiety in rolipram resulting in the discovery of 8-methoxyquinoline-5-carboxamides as potent inhibitors of phosphodiesterase type 4 (PDE4).
Asunto(s)
3',5'-AMP Cíclico Fosfodiesterasas/antagonistas & inhibidores , Amidas/uso terapéutico , Antiasmáticos/uso terapéutico , Asma/tratamiento farmacológico , Inhibidores de Fosfodiesterasa/uso terapéutico , Amidas/farmacología , Antiasmáticos/farmacología , Fosfodiesterasas de Nucleótidos Cíclicos Tipo 4 , Humanos , Inhibidores de Fosfodiesterasa/farmacologíaRESUMEN
The synthesis and pharmacological profile of a novel series of 2-substituted 8-methoxyquinolines is described. The 2-trifluoromethyl compound was found to be a potent inhibitor of phosphodiesterase type 4 (PDE4).
Asunto(s)
3',5'-AMP Cíclico Fosfodiesterasas/antagonistas & inhibidores , Inhibidores de Fosfodiesterasa/síntesis química , Inhibidores de Fosfodiesterasa/farmacología , Quinolinas/síntesis química , Quinolinas/farmacología , Animales , Área Bajo la Curva , Fosfodiesterasas de Nucleótidos Cíclicos Tipo 4 , Cobayas , Inhibidores de Fosfodiesterasa/farmacocinética , Quinolinas/farmacocinética , Vómitos/inducido químicamenteRESUMEN
The synthesis and pharmacological profile of a novel series of 7-methoxy-furo[2,3-c]pyridine-4-carboxamides is described. Some of these compounds were found to be potent inhibitors of phosphodiesterase type 4 (PDE4).
Asunto(s)
3',5'-AMP Cíclico Fosfodiesterasas/antagonistas & inhibidores , Antiasmáticos/síntesis química , Antiasmáticos/farmacología , Furanos/síntesis química , Furanos/farmacología , Inhibidores de Fosfodiesterasa/síntesis química , Inhibidores de Fosfodiesterasa/farmacología , Piridinas/síntesis química , Piridinas/farmacología , Animales , Antiasmáticos/farmacocinética , Sitios de Unión , Fosfodiesterasas de Nucleótidos Cíclicos Tipo 4 , Furanos/farmacocinética , Cobayas , Indicadores y Reactivos , Inhibidores de Fosfodiesterasa/farmacocinética , Piridinas/farmacocinética , Rolipram/metabolismo , Relación Estructura-ActividadRESUMEN
The syntheses and pharmacological profiles of some 2-trifluoromethyl-8-methoxyquinoline-5-carboxamides are described. SCH351591 is a potent selective inhibitor of phosphodiesterase type 4 (PDE4).