RESUMEN
A series of acyloxyalkyl and amidooxyalkyl ketones appended to a carbobenzyloxy aspartic acid core have been prepared. The most potent of these new inhibitors was 4i with a K(i) of 0.5 microM. These two series provide an improved understanding of the binding requirements for the hydrophobic prime side of ICE.
Asunto(s)
Inhibidores de Caspasas , Inhibidores de Cisteína Proteinasa/farmacología , Cetonas/farmacología , Humanos , Modelos Moleculares , Monocitos/efectos de los fármacosRESUMEN
A series of sulfonamides (1) has been prepared as inhibitors of interleukin-1beta converting enzyme (ICE), also known as caspase 1. These compounds were designed to improve potency by rigidifying the enzyme bound molecule through an intramolecular hydrogen bond. An X-ray crystal structure of a representative member of this series bound to the active site of ICE, confirms the presence of the hydrogen bonding interaction.
Asunto(s)
Inhibidores de Caspasas , Diseño de Fármacos , Serpinas/síntesis química , Serpinas/farmacología , Sulfonamidas/síntesis química , Sulfonamidas/farmacología , Proteínas Virales , Sitios de Unión , Caspasa 1/metabolismo , Cristalografía por Rayos X , Humanos , Enlace de Hidrógeno , Modelos Moleculares , Conformación Molecular , Estructura Molecular , Relación Estructura-ActividadRESUMEN
A novel class of reversible inhibitors of Interleukin-1beta-converting enzyme (ICE, caspase-1) were discovered by iterative structure-based design. Guided by the X-ray crystal structure of analogues 1, 7 and 10 bound to ICE, we have designed a nonpeptide series of small molecule inhibitors. These compounds incorporate an arylsulfonamide moiety which replaces Val-His unit (P3-P2 residues) amino acids of the native substrate. The synthesis of the core structure, structure-activity relationships (SARs), and proposed binding orientation based on molecular modeling studies for this series of ICE inhibitors are described.
