RESUMEN
Imidazo-[1, 2-a]pyrazine 1 is a potent inhibitor of Aurora A and B kinase in vitro and is effective in in vivo tumor models, but has poor oral bioavailbility and is unsuitable for oral dosing. We describe herein our effort to improve oral exposure in this class, resulting ultimately in the identification of a potent Aurora inhibitor 16, which exhibited good drug exposure levels across species upon oral dosing, and showed excellent in vivo efficacy in a mouse xenograft tumor model when dosed orally.
Asunto(s)
Antineoplásicos/uso terapéutico , Aurora Quinasa A/antagonistas & inhibidores , Aurora Quinasa B/antagonistas & inhibidores , Imidazoles/uso terapéutico , Inhibidores de Proteínas Quinasas/uso terapéutico , Pirazinas/uso terapéutico , Administración Oral , Animales , Antineoplásicos/administración & dosificación , Antineoplásicos/síntesis química , Antineoplásicos/farmacocinética , Perros , Células HCT116 , Haplorrinos , Histonas/metabolismo , Humanos , Imidazoles/administración & dosificación , Imidazoles/síntesis química , Imidazoles/farmacocinética , Ratones , Fosforilación , Inhibidores de Proteínas Quinasas/administración & dosificación , Inhibidores de Proteínas Quinasas/síntesis química , Inhibidores de Proteínas Quinasas/farmacocinética , Pirazinas/administración & dosificación , Pirazinas/síntesis química , Pirazinas/farmacocinética , Ratas , Estereoisomerismo , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
The optimization of oxazole-based PDE4 inhibitor 1 has led to the identification of both oral (compound 16) and inhaled (compound 34) PDE4 inhibitors. Selectivity against PDE10/PDE11, off target screening, and in vivo activity in the rat are discussed.
Asunto(s)
Fosfodiesterasas de Nucleótidos Cíclicos Tipo 4/química , Oxazoles/química , Prolina/análogos & derivados , Quinolinas/síntesis química , Administración Oral , Animales , Fosfodiesterasas de Nucleótidos Cíclicos Tipo 4/metabolismo , Evaluación Preclínica de Medicamentos , Semivida , Inhalación , Oxazoles/síntesis química , Oxazoles/farmacocinética , Inhibidores de Fosfodiesterasa 4/síntesis química , Inhibidores de Fosfodiesterasa 4/química , Inhibidores de Fosfodiesterasa 4/farmacocinética , Prolina/síntesis química , Prolina/química , Prolina/farmacocinética , Quinolinas/química , Quinolinas/farmacocinética , Ratas , Ratas Sprague-Dawley , Relación Estructura-ActividadRESUMEN
The introduction of A ring pyrazole modification to the hydrocortisone C-21 heteroaryl thioethers generated compounds with excellent transrepression potency (IL-8 inhibition) compared to their hydrocortisone analogs. However, the transcriptional transactivation activity of these compounds were considerably higher than the corresponding hydrocortisone analogs. Among all the compounds evaluated, a quinoxaline thioether modification demonstrated the best overall in vitro separation.
Asunto(s)
Receptores de Glucocorticoides/efectos de los fármacos , Esteroides/química , Sulfuros/química , Humanos , Hidrocortisona , Pirazoles/química , Relación Estructura-Actividad , Sulfuros/farmacología , Activación Transcripcional/efectos de los fármacosRESUMEN
The prednisolone C-21 heteroaryl thioethers have been synthesized and evaluated in cell based transrepression and transactivation assays. Most of the compounds demonstrated weak transactivational activity in both human and rat tyrosineaminotransferase functional assay while keeping potent anti-inflammatory activity. The benzimidazole thioether 7 exhibited comparable anti-inflammatory activity and improved safety profile compared to the classical oral steroid prednisolone.
Asunto(s)
Antiinflamatorios no Esteroideos/farmacología , Descubrimiento de Drogas , Receptores de Glucocorticoides/agonistas , Sulfuros/farmacología , Administración Oral , Animales , Antiinflamatorios no Esteroideos/administración & dosificación , Antiinflamatorios no Esteroideos/química , Disponibilidad Biológica , Línea Celular , Relación Dosis-Respuesta a Droga , Células Hep G2 , Humanos , Conformación Molecular , Ratas , Ratas Endogámicas BN , Receptores de Glucocorticoides/metabolismo , Estereoisomerismo , Relación Estructura-Actividad , Sulfuros/administración & dosificación , Sulfuros/química , Tirosina Transaminasa/metabolismoRESUMEN
Optimization of oxazole-based PDE4 inhibitors has led to the discovery of a series of quinolyl oxazoles, with 4-benzylcarboxamide and 5-α-aminoethyl groups which exhibit picomolar potency against PDE4. Selectivity profiles and in vivo biological activity are also reported.
Asunto(s)
Antiinflamatorios/síntesis química , Fosfodiesterasas de Nucleótidos Cíclicos Tipo 4/química , Oxazoles/síntesis química , Inhibidores de Fosfodiesterasa 4/síntesis química , Quinolinas/síntesis química , Animales , Antiinflamatorios/farmacología , Óxidos N-Cíclicos/química , Fosfodiesterasas de Nucleótidos Cíclicos Tipo 4/metabolismo , Descubrimiento de Drogas , Humanos , Modelos Moleculares , Oxazoles/farmacología , Inhibidores de Fosfodiesterasa 4/farmacología , Quinolinas/química , Quinolinas/farmacología , Ratas , Relación Estructura-Actividad , Factor de Necrosis Tumoral alfa/antagonistas & inhibidoresRESUMEN
A series of C-21 mercapto derivatives of hydrocortisone have been synthesized and evaluated in cell based transrepression and transactivation assays. The benzothiazole derivative, compound 6 not only showed a dissociated profile in vitro functional assays but also a pharmacological profile in a Brown-Norway rat therapeutic index model of asthma that dissociated side effects (thymolysis) while maintaining efficacy against pulmonary inflammation and lung function.
Asunto(s)
Esteroides/farmacología , Compuestos de Sulfhidrilo/química , Administración por Inhalación , Animales , Asma/tratamiento farmacológico , Línea Celular , Descubrimiento de Drogas , Pulmón/efectos de los fármacos , Ratas , Esteroides/administración & dosificación , Esteroides/química , Esteroides/uso terapéutico , Relación Estructura-ActividadRESUMEN
Oral administration is the most desirable route of drug delivery for systemically active drugs. Oral drugs must possess a certain level of oral bioavailability, which is a product of oral absorption and first-pass effect. Low oral bioavailability may be attributed to poor absorption and/or high first-pass hepatic elimination. In the lead optimization stage of drug discovery, if the relative contribution of oral absorption and metabolism could be discerned for poorly bioavailable compounds, a path forward for remedy would be possible. This report describes an approach utilizing oral/intravenous pharmacokinetic data to estimate oral absorption. The fraction of dose absorbed is calculated as the ratio of the actual bioavailable fraction to the maximum bioavailable fraction estimated from systemic clearance. An arbitrary classification was devised where low absorption encompasses compounds whose extent of absorption is
Asunto(s)
Descubrimiento de Drogas , Preparaciones Farmacéuticas/metabolismo , Farmacocinética , Absorción , Administración Oral , Animales , Área Bajo la Curva , Disponibilidad Biológica , Fenómenos Químicos , Perros , Evaluación Preclínica de Medicamentos , Inyecciones Intravenosas , Macaca fascicularis , Masculino , Tasa de Depuración Metabólica , Peso Molecular , Preparaciones Farmacéuticas/química , Ratas , Ratas Sprague-Dawley , Especificidad de la Especie , Distribución TisularRESUMEN
Substituted quinolyl oxazoles were discovered as a novel and highly potent series of phosphodiesterase 4 (PDE4) inhibitors. Structure-activity relationship studies revealed that the oxazole core, with 4-carboxamide and 5-aminomethyl groups, is a novel PDE4 inhibitory pharmacophore. Selectivity profiles and in vivo biological activity are also reported.