RESUMO
An effort aimed at exploring structural diversity in the N-pyrazole-N'-naphthylurea class of p38 kinase inhibitors led to the synthesis and characterization of N-phenyl-N'-naphthylureas. Examples of these compounds displayed excellent inhibition of TNF-alpha production in vitro, as well as efficacy in a mouse model of lipopolysaccharide induced endotoxemia. In addition, perspective is provided on the role of a sulfonamide functionality in defining inhibitor potency.
Assuntos
2-Naftilamina/análogos & derivados , Inibidores de Proteínas Quinases/farmacologia , Ureia/análogos & derivados , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo , 2-Naftilamina/química , Animais , Química Orgânica/métodos , Química Farmacêutica/métodos , Cristalografia por Raios X/métodos , Desenho de Fármacos , Concentração Inibidora 50 , Lipopolissacarídeos/metabolismo , Camundongos , Modelos Químicos , Estrutura Molecular , Fator de Necrose Tumoral alfa/metabolismo , Ureia/químicaRESUMO
High-throughput screening is routinely employed as a method for the identification of novel hit structures. Large numbers of active compounds are typically procured in this way and must undergo a rigorous validation process. This process is described in detail for a collection of screening hits identified as inhibitors of IkappaB kinase-beta (IKKbeta), a key regulatory enzyme in the nuclear factor-kappaB (NF-kappaB) pathway. From these studies, a promising hit series was selected. Subsequent lead generation activities included the development of a pharmacophore hypothesis and structure-activity relationship (SAR) for the hit series. This led to the exploration of related scaffolds offering additional opportunities, and the various structural classes were comparatively evaluated for enzyme inhibition, selectivity, and drug-like properties. A novel lead series of thienopyridines was thereby established, and this series advanced into lead optimization for further development.
Assuntos
Quinase I-kappa B/antagonistas & inibidores , Quinase I-kappa B/química , Modelos Moleculares , Piridinas/síntese química , Oxazóis/síntese química , Oxazóis/química , Piridinas/química , Relação Estrutura-AtividadeRESUMO
The formation and stereoselective quenching of 1-mannopyranosyl radicals by a tributyltin hydride-mediated intramolecular 1,5-hydrogen abstraction sequence is described. A competing process is 1,4-hydrogen atom abstraction leading principally to glucopyran-2-ulosides. Fragmentation of the anomeric radical resulting in the formation of ring opened products is a problem in certain series. The chemistry is dictated to a considerable extent by the nature of the protecting groups employed with the 4,6-benzylidene series and, for rhamnose, the Ley 3,4-dispiroketal, being particularly susceptible to the 1,4-hydrogen atom abstraction but less to the fragmentation. Photochemical conditions are described, in which these side reactions are practically eliminated, and applied to the inversion of an alpha- to a beta-mannoside in a disaccharide.