RESUMEN
Matrix metalloproteinase-9 (MMP-9) is a secreted zinc-dependent endopeptidase that degrades the extracellular matrix and basement membrane of neurons, and then contributes to synaptic plasticity by remodeling the extracellular matrix. Inhibition of MMP-9 activity has therapeutic potential for neurodegenerative diseases such as fragile X syndrome. This paper reports the molecular design, synthesis, and in vitro studies of novel indole derivatives as inhibitors of proMMP-9 activation. High-throughput screening (HTS) of our internal compound library and subsequent merging of hit compounds 1 and 2 provided compound 4 as a bona-fide lead. X-ray structure-based design and subsequent lead optimization led to the discovery of compound 33, a highly potent and selective inhibitor of proMMP-9 activation.
Asunto(s)
Precursores Enzimáticos , Metaloproteinasa 9 de la Matriz , Metaloproteinasa 9 de la Matriz/metabolismo , Precursores Enzimáticos/metabolismo , Matriz Extracelular/metabolismo , Indoles/farmacología , Indoles/metabolismo , Metaloendopeptidasas/metabolismo , Inhibidores de la Metaloproteinasa de la MatrizRESUMEN
Class I phosphoinositide 3-kinases (PI3Ks), particularly PI3Kγ, have become attractive drug targets for inflammatory and autoimmune disorders such as rheumatoid arthritis. Herein, we describe the synthesis and the structure-activity relationships (SAR) of a series of 2-amino-5-oxadiazolyl thiazoles, culminating in the identification of 8j (TASP0415914), an orally potent inhibitor of phosphoinositide 3-kinase γ (PI3Kγ). TASP0415914 demonstrated good potency in a cell-based assay and, furthermore, exhibited in vivo efficacy in a collagen induced arthritis (CIA) model in mice after oral administration.
Asunto(s)
Artritis Experimental/tratamiento farmacológico , Descubrimiento de Drogas , Inhibidores Enzimáticos/farmacología , Oxadiazoles/farmacología , Inhibidores de las Quinasa Fosfoinosítidos-3 , Tiazoles/farmacología , Administración Oral , Animales , Artritis Experimental/inducido químicamente , Artritis Experimental/enzimología , Fosfatidilinositol 3-Quinasa Clase Ib/metabolismo , Colágeno , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Inhibidores Enzimáticos/administración & dosificación , Inhibidores Enzimáticos/química , Masculino , Ratones , Ratones Endogámicos DBA , Estructura Molecular , Oxadiazoles/administración & dosificación , Oxadiazoles/química , Relación Estructura-Actividad , Tiazoles/administración & dosificación , Tiazoles/químicaRESUMEN
A novel series of 2-aminothiazole-oxazoles was designed and synthesized as part of efforts to develop potent phosphoinositide 3-kinase γ (PI3Kγ) inhibitors. The modification of a high-throughput screening hit, compound 1, resulted in the identification of compounds 10 and 15, which displayed potent inhibitory activities in enzyme-based and cell-based assays.
Asunto(s)
Descubrimiento de Drogas , Oxazoles/farmacología , Inhibidores de las Quinasa Fosfoinosítidos-3 , Inhibidores de Proteínas Quinasas/farmacología , Tiazoles/farmacología , Animales , Fosfatidilinositol 3-Quinasa Clase Ib/metabolismo , Cristalografía por Rayos X , Relación Dosis-Respuesta a Droga , Ensayos Analíticos de Alto Rendimiento , Macrófagos/efectos de los fármacos , Macrófagos/enzimología , Macrófagos/metabolismo , Ratones , Modelos Moleculares , Estructura Molecular , Oxazoles/química , Inhibidores de Proteínas Quinasas/síntesis química , Inhibidores de Proteínas Quinasas/química , Relación Estructura-Actividad , Tiazoles/químicaRESUMEN
A series of 5-(1,3-benzothiazol-6-yl)-4-(4-methyl-1,3-thiazol-2-yl)-1H-imidazole derivatives was synthesized as transforming growth factor-ß (TGF-ß) type I receptor (also known as activin-like kinase 5 or ALK5) inhibitors. These compounds were evaluated for their ALK5 inhibitory activity in an enzyme assay and for their TGF-ß-induced Smad2/3 phosphorylation inhibitory activity in a cell-based assay. As a representative compound, 16i was a potent and selective ALK5 inhibitor, exhibiting a good enzyme inhibitory activity (IC(50) = 5.5 nM) as well as inhibitory activity against TGF-ß-induced Smad2/3 phosphorylation at a cellular level (IC(50) = 36 nM). Furthermore, the topical application of 3% 16i lotion significantly inhibited Smad2 phosphorylation in Mouse skin (90% inhibition compared with vehicle-treated animals).
Asunto(s)
Imidazoles/farmacología , Proteínas Serina-Treonina Quinasas/antagonistas & inhibidores , Receptores de Factores de Crecimiento Transformadores beta/antagonistas & inhibidores , Animales , Femenino , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Proteínas Serina-Treonina Quinasas/química , Receptor Tipo I de Factor de Crecimiento Transformador beta , Receptores de Factores de Crecimiento Transformadores beta/químicaRESUMEN
We have described the synthesis, enzyme inhibitory activity, structure-activity relationships, and proposed binding mode of a novel series of pyrrole derivatives as lymphocyte-specific kinase (Lck) inhibitors. The most potent analogs exhibited good enzyme inhibitory activity (IC(50)s <10nM) for Lck kinase inhibition.
Asunto(s)
Proteína Tirosina Quinasa p56(lck) Específica de Linfocito/antagonistas & inhibidores , Inhibidores de Proteínas Quinasas/síntesis química , Pirroles/síntesis química , Adenosina Trifosfato/química , Sitios de Unión , Simulación por Computador , Cristalografía por Rayos X , Enlace de Hidrógeno , Proteína Tirosina Quinasa p56(lck) Específica de Linfocito/metabolismo , Linfocitos/efectos de los fármacos , Linfocitos/metabolismo , Inhibidores de Proteínas Quinasas/química , Inhibidores de Proteínas Quinasas/farmacología , Pirroles/química , Pirroles/farmacología , Relación Estructura-ActividadRESUMEN
We have identified a novel series of ring-fused pyrazole derivatives as lymphocyte-specific kinase (Lck) inhibitors. The most potent analogs exhibited good enzyme inhibitory activity (IC(50)s <1nM) as well as excellent cellular activity against mixed lymphocyte reaction (MLR) (IC(50)s <1nM).
Asunto(s)
Proteína Tirosina Quinasa p56(lck) Específica de Linfocito/antagonistas & inhibidores , Inhibidores de Proteínas Quinasas/síntesis química , Pirroles/química , Adenosina Trifosfato/química , Sitios de Unión , Simulación por Computador , Cristalografía por Rayos X , Enlace de Hidrógeno , Proteína Tirosina Quinasa p56(lck) Específica de Linfocito/metabolismo , Linfocitos/efectos de los fármacos , Linfocitos/metabolismo , Inhibidores de Proteínas Quinasas/química , Inhibidores de Proteínas Quinasas/farmacología , Pirroles/síntesis química , Pirroles/farmacología , Relación Estructura-ActividadRESUMEN
Racemic 1- and 2-naphthylmethoxyacetic acids (1NMA and 2NMA), the chiral anisotropic reagents used for absolute configuration determination of chiral secondary alcohols and primary amines, were conveniently resolved to enantiomers (>99% ee) by condensation with L-phenylalaninol (2-amino-3-phenylpropanol), chromatographic separation of the diastereomers, and hydrolysis. This method enables large-scale preparation of enantiomeric 1NMA and 2NMA.