RESUMEN
A novel, potent and selective quinazolinone series of inhibitors of p38α MAP kinase has been identified. Modifications designed to address the issues of poor aqueous solubility and high plasma protein binding as well as embedded aniline functionalities resulted in the identification of a clinical candidate N-cyclopropyl-4-methyl-3-[6-(4-methylpiperazin-1-yl)-4-oxoquinazolin-3(4H)-yl]benzamide (AZD6703). Optimisation was guided by understanding of the binding modes from X-ray crystallographic studies which showed a switch from DFG 'out' to DFG 'in' as the inhibitor size was reduced to improve overall properties.
Asunto(s)
Antiinflamatorios no Esteroideos/síntesis química , Proteína Quinasa 14 Activada por Mitógenos/antagonistas & inhibidores , Piperazinas/síntesis química , Inhibidores de Proteínas Quinasas/síntesis química , Animales , Antiinflamatorios no Esteroideos/química , Antiinflamatorios no Esteroideos/farmacología , Proteínas Sanguíneas/química , Cristalografía por Rayos X , Perros , Descubrimiento de Drogas , Humanos , Inflamación/tratamiento farmacológico , Proteína Quinasa 14 Activada por Mitógenos/metabolismo , Modelos Moleculares , Peso Molecular , Piperazinas/química , Piperazinas/farmacología , Unión Proteica , Inhibidores de Proteínas Quinasas/química , Inhibidores de Proteínas Quinasas/farmacología , Ratas , Solubilidad , Relación Estructura-ActividadRESUMEN
A valid PLS-DA model to predict attrition in pre-clinical toxicology for basic oral candidate drugs was built. A combination of aromatic/aliphatic balance, flatness, charge distribution and size descriptors helped predict the successful progression of compounds through a wide range of toxicity testing. Eighty percent of an independent test set of marketed post-2000 basic drugs could be successfully classified using the model, indicating useful forward predictivity. The themes within this work provide additional guidance for medicinal design chemists and complement other literature property guidelines.
Asunto(s)
Diseño de Fármacos , Evaluación Preclínica de Medicamentos/métodos , Industria Farmacéutica/métodos , Modelos Estadísticos , Pruebas de Toxicidad/métodos , Animales , Análisis Discriminante , Humanos , Estructura Molecular , Preparaciones Farmacéuticas/química , Preparaciones Farmacéuticas/metabolismoRESUMEN
The total synthesis of the cytotoxic antitumour natural product epothilone C has provided a stage for the exploitation and further development of immobilized reagent methods. A stereoselective convergent synthetic strategy was applied, incorporating polymer-supported reagents, catalysts, scavengers and catch-and-release techniques to avoid frequent aqueous work-up and chromatographic purification.
Asunto(s)
Epotilonas/síntesis química , Antineoplásicos/síntesis química , Antineoplásicos/química , Factores Biológicos/síntesis química , Factores Biológicos/química , Epotilonas/química , Macrólidos/síntesis química , Macrólidos/química , Estructura Molecular , Polímeros/química , EstereoisomerismoRESUMEN
A novel p38 MAP kinase inhibitor structural class was discovered through selectivity screening. The rational analogue design, synthesis and structure-activity relationship of this series of bis-amide inhibitors is reported. The inhibition in vitro of human p38alpha enzyme activity and lipopolysaccharide-induced tumour necrosis factor-alpha release is described for the series. The activity in vivo and pharmacokinetic properties are exemplified for the more potent analogues.