RESUMO
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.
Assuntos
Anti-Inflamatórios não Esteroides/síntese química , Proteína Quinase 14 Ativada por Mitógeno/antagonistas & inibidores , Piperazinas/síntese química , Inibidores de Proteínas Quinases/síntese química , Animais , Anti-Inflamatórios não Esteroides/química , Anti-Inflamatórios não Esteroides/farmacologia , Proteínas Sanguíneas/química , Cristalografia por Raios X , Cães , Descoberta de Drogas , Humanos , Inflamação/tratamento farmacológico , Proteína Quinase 14 Ativada por Mitógeno/metabolismo , Modelos Moleculares , Peso Molecular , Piperazinas/química , Piperazinas/farmacologia , Ligação Proteica , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacologia , Ratos , Solubilidade , Relação Estrutura-AtividadeRESUMO
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.
Assuntos
Desenho de Fármacos , Avaliação Pré-Clínica de Medicamentos/métodos , Indústria Farmacêutica/métodos , Modelos Estatísticos , Testes de Toxicidade/métodos , Animais , Análise Discriminante , Humanos , Estrutura Molecular , Preparações Farmacêuticas/química , Preparações Farmacêuticas/metabolismoRESUMO
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.
Assuntos
Amidas/síntese química , Antirreumáticos/síntese química , Proteínas Quinases p38 Ativadas por Mitógeno/antagonistas & inibidores , Amidas/farmacocinética , Amidas/farmacologia , Animais , Antirreumáticos/farmacocinética , Antirreumáticos/farmacologia , Artrite Reumatoide/tratamento farmacológico , Humanos , Técnicas In Vitro , Leucócitos Mononucleares/efeitos dos fármacos , Leucócitos Mononucleares/metabolismo , Lipopolissacarídeos/farmacologia , Camundongos , Camundongos Endogâmicos BALB C , Ratos , Relação Estrutura-Atividade , Fatores de Tempo , Fator de Necrose Tumoral alfa/antagonistas & inibidoresRESUMO
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.
