RESUMO
Novel potent and selective diarylimidazole inhibitors of p38 MAP (mitogen-activated protein) kinase are described which have activity in both cell-based assays of tumor necrosis factor-alpha (TNF-alpha) release and an animal model of rheumatoid arthritis. The SAR leading to the development of selectivity against c-Raf and JNK2alpha1 kinases is presented, with key features being substitution of the 4-aryl ring with m-trifluoromethyl and substitution of the 5-heteroaryl ring with a 2-amino substituent. Cell-based activity was significantly enhanced by incorporation of a 4-piperidinyl moiety at the 2-position of the imidazole which also enhanced aqueous solubility. In general, oral bioavailability of this class of compounds was found to be poor unless the imidazole was methylated on nitrogen. This work led to identification of 48, a potent (p38 MAP kinase inhibition IC50 0.24 nM) and selective p38 MAP kinase inhibitor which inhibits lipopolysaccharide-stimulated release of TNF-alpha from human blood with an IC50 2.2 nM, shows good oral bioavailability in rat and rhesus monkey, and demonstrates significant improvement in measures of disease progression in a rat adjuvant-induced arthritis model.
Assuntos
Aminopiridinas/síntese química , Proteínas Quinases Dependentes de Cálcio-Calmodulina/antagonistas & inibidores , Inibidores Enzimáticos/síntese química , Imidazóis/síntese química , Proteínas Quinases Ativadas por Mitógeno , Administração Oral , Aminopiridinas/química , Aminopiridinas/farmacocinética , Aminopiridinas/farmacologia , Animais , Artrite Experimental/tratamento farmacológico , Disponibilidade Biológica , Desenho de Fármacos , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacocinética , Inibidores Enzimáticos/farmacologia , Feminino , Humanos , Imidazóis/química , Imidazóis/farmacocinética , Imidazóis/farmacologia , Macaca mulatta , Camundongos , Ratos , Estimulação Química , Relação Estrutura-Atividade , Fator de Necrose Tumoral alfa/biossíntese , Proteínas Quinases p38 Ativadas por MitógenoRESUMO
Taxol, a substance originally isolated from the Pacific yew tree (Taxus brevifolia) more than two decades ago, has recently been approved for the clinical treatment of cancer patients. Hailed as having provided one of the most significant advances in cancer therapy, this molecule exerts its anticancer activity by inhibiting mitosis through enhancement of the polymerization of tubulin and consequent stabilization of microtubules. The scarcity of taxol and the ecological impact of harvesting it have prompted extension searches for alternative sources including semisynthesis, cellular culture production and chemical synthesis. The latter has been attempted for almost two decades, but these attempts have been thwarted by the magnitude of the synthetic challenge. Here we report the total synthesis of taxol by a convergent strategy, which opens a chemical pathway for the production of both the natural product itself and a variety of designed taxoids.
