RESUMO
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.
Assuntos
Cicatriz/prevenção & controle , Descoberta de Drogas , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacologia , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Piridinas/química , Piridinas/farmacologia , Receptores de Fatores de Crescimento Transformadores beta/antagonistas & inibidores , Pele/efeitos dos fármacos , Animais , Modelos Moleculares , Fosforilação , Ratos , Receptor do Fator de Crescimento Transformador beta Tipo IRESUMO
(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.
Assuntos
Antibacterianos/química , Antibacterianos/farmacologia , Fluoroquinolonas/química , Fluoroquinolonas/farmacologia , Nitrilas/química , Nitrilas/síntese química , Pirrolidinas/química , Pirrolidinas/síntese química , Catálise , Estrutura Molecular , EstereoisomerismoRESUMO
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.
Assuntos
Antibacterianos , Bactérias Gram-Negativas/efeitos dos fármacos , Bactérias Gram-Negativas/enzimologia , Bactérias Gram-Positivas/efeitos dos fármacos , Bactérias Gram-Positivas/enzimologia , Quinazolinonas , Inibidores da Topoisomerase II , Antibacterianos/síntese química , Antibacterianos/química , Antibacterianos/farmacologia , Técnicas de Química Combinatória , Fluoroquinolonas/síntese química , Fluoroquinolonas/química , Fluoroquinolonas/farmacologia , Testes de Sensibilidade Microbiana , Estrutura Molecular , Quinazolinonas/síntese química , Quinazolinonas/química , Quinazolinonas/farmacologia , Relação Estrutura-AtividadeRESUMO
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).
Assuntos
Antibacterianos/síntese química , Quinazolinonas/síntese química , Quinazolinonas/farmacologia , Inibidores da Topoisomerase II , Aminas/química , Aminas/farmacologia , Antibacterianos/química , DNA Girase , Bactérias Gram-Positivas/efeitos dos fármacos , Concentração Inibidora 50 , Quinazolinonas/química , Relação Estrutura-AtividadeRESUMO
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.
Assuntos
Antibacterianos/síntese química , Antibacterianos/farmacologia , Bactérias/efeitos dos fármacos , Quinazolinonas/síntese química , DNA Topoisomerase IV/antagonistas & inibidores , Farmacorresistência Bacteriana Múltipla/efeitos dos fármacos , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacologia , Bactérias Gram-Negativas/efeitos dos fármacos , Bactérias Gram-Positivas/efeitos dos fármacos , Resistência a Meticilina , Testes de Sensibilidade Microbiana , Relação Estrutura-Atividade , Inibidores da Topoisomerase IIRESUMO
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.