RESUMEN
A series of 2-(1H-pyrazol-1-yl)pyridines are described as inhibitors of ALK5 (TGFß receptor I kinase). Modeling compounds in the ALK5 kinase domain enabled some optimization of potency via substitutions on the pyrazole core. One of these compounds PF-03671148 gave a dose dependent reduction in TGFß induced fibrotic gene expression in human fibroblasts. A similar reduction in fibrotic gene expression was observed when PF-03671148 was applied topically in a rat wound repair model. Thus these compounds have potential utility for the prevention of dermal scarring.
Asunto(s)
Cicatriz/prevención & control , Descubrimiento de Drogas , Inhibidores de Proteínas Quinasas/química , Inhibidores de Proteínas Quinasas/farmacología , Proteínas Serina-Treonina Quinasas/antagonistas & inhibidores , Piridinas/química , Piridinas/farmacología , Receptores de Factores de Crecimiento Transformadores beta/antagonistas & inhibidores , Piel/efectos de los fármacos , Animales , Modelos Moleculares , Fosforilación , Ratas , Receptor Tipo I de Factor de Crecimiento Transformador betaRESUMEN
(S)-3-(methylamino)-3-((R)-pyrrolidin-3-yl)propanenitrile (1) is a key intermediate in the preparation of PF-00951966, (1) a fluoroquinolone antibiotic for use against key pathogens causing community-acquired respiratory tract infections including multidrug resistant (MDR) organisms. The current work describes the development of a highly efficient and stereoselective synthesis of 1 in 10 steps with an overall yield of 24% from readily available benzyloxyacetyl chloride. Two key transformations in the synthetic sequence involve (a) catalytic asymmetric hydrogenation with chiral DM-SEGPHOS-Ru(II) complex to afford ß-hydroxy amide 11b in good yield (73%) and high stereoselectivity (de 98%, ee >99%) after recrystallization and (b) S(N)2 substitution reaction with methylamine to provide diamine 14 with inversion of configuration at the 1'-position in high yield (80%), after efficient purification using a simple acid/base extraction protocol.
Asunto(s)
Antibacterianos/química , Antibacterianos/farmacología , Fluoroquinolonas/química , Fluoroquinolonas/farmacología , Nitrilos/química , Nitrilos/síntesis química , Pirrolidinas/química , Pirrolidinas/síntesis química , Catálisis , Estructura Molecular , EstereoisomerismoRESUMEN
A novel series of bacterial topoisomerase (3-aminoquinazolinediones) inhibitors are described. The side-chain SAR against Gram-positive and Gram-negative organisms as well as DNA gyrase activity is reported.
Asunto(s)
Antibacterianos , Bacterias Gramnegativas/efectos de los fármacos , Bacterias Gramnegativas/enzimología , Bacterias Grampositivas/efectos de los fármacos , Bacterias Grampositivas/enzimología , Quinazolinonas , Inhibidores de Topoisomerasa II , Antibacterianos/síntesis química , Antibacterianos/química , Antibacterianos/farmacología , Técnicas Químicas Combinatorias , Fluoroquinolonas/síntesis química , Fluoroquinolonas/química , Fluoroquinolonas/farmacología , Pruebas de Sensibilidad Microbiana , Estructura Molecular , Quinazolinonas/síntesis química , Quinazolinonas/química , Quinazolinonas/farmacología , Relación Estructura-ActividadRESUMEN
A series of 3-aminoquinazolinediones was synthesized and evaluated for its antibacterial and DNA gyrase activity. The SAR around the quinazolinedione core was explored and the optimal substitutions were combined to give two compounds, 2r and 2s, with exceptional enzyme potency (IC50 = 0.2 microM) and activity against gram-positive organisms (MIC's = 0.015-0.06 microg/mL).
Asunto(s)
Antibacterianos/síntesis química , Quinazolinonas/síntesis química , Quinazolinonas/farmacología , Inhibidores de Topoisomerasa II , Aminas/química , Aminas/farmacología , Antibacterianos/química , Girasa de ADN , Bacterias Grampositivas/efectos de los fármacos , Concentración 50 Inhibidora , Quinazolinonas/química , Relación Estructura-ActividadRESUMEN
The 3-aminoquinzolinediones represent a new series of antibacterial agents structurally related to the fluoroquinolones. They are inhibitors of bacterial gyrase and topoisomerase IV and demonstrate clinically useful antibacterial activity against fastidious Gram-negative and Gram-positive organisms, including multidrug- and fluoroquinolone-resistant organisms. These agents also demonstrate in vivo efficacy in murine systemic infection models.
Asunto(s)
Antibacterianos/síntesis química , Antibacterianos/farmacología , Bacterias/efectos de los fármacos , Quinazolinonas/síntesis química , Topoisomerasa de ADN IV/antagonistas & inhibidores , Farmacorresistencia Bacteriana Múltiple/efectos de los fármacos , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/farmacología , Bacterias Gramnegativas/efectos de los fármacos , Bacterias Grampositivas/efectos de los fármacos , Resistencia a la Meticilina , Pruebas de Sensibilidad Microbiana , Relación Estructura-Actividad , Inhibidores de Topoisomerasa IIRESUMEN
A series of 3-hydroxyquinazoline-2,4-diones was synthesized and evaluated for antibacterial activity. This series represents a novel addition to the DNA gyrase inhibitor class of antibacterials. Appropriate substitutions onto the core template yielded compounds with excellent potency against E. coli gyrase and significant in vitro Gram-negative and Gram-positive antibacterial activity.