RESUMEN
Avibactam is a diazabicyclooctane ß-lactamase inhibitor possessing outstanding but incomplete efficacy against multidrug-resistant Gram-negative pathogens in combination with ß-lactam antibiotics. Significant pharmaceutical investment in generating derivatives of avibactam warrants a thorough characterization of their activity. We show here through structural and kinetic analysis that select diazabicyclooctane derivatives display effective but varied inhibition of two clinically important ß-lactamases (CTX-M-15 and OXA-48). Furthermore, these derivatives exhibit considerable antimicrobial activity (MIC ≤ 2 µg/mL) against clinical isolates of Pseudomonas aeruginosa, Escherichia coli, and Enterobacter spp. Imaging of cell phenotype along with structural and biochemical experiments unambiguously demonstrate that this activity, in E. coli, is a result of targeting penicillin-binding protein 2. Our results suggest that structure-activity relationship studies for the purpose of drug discovery must consider both ß-lactamases and penicillin-binding proteins as targets. We believe that this approach will yield next-generation combination or monotherapies with an expanded spectrum of activity against currently untreatable Gram-negative pathogens.
Asunto(s)
Compuestos de Azabiciclo/química , Compuestos de Azabiciclo/farmacología , Proteínas de Unión a las Penicilinas/metabolismo , Inhibidores de beta-Lactamasas/química , Inhibidores de beta-Lactamasas/farmacología , Cinética , Pruebas de Sensibilidad Microbiana , Conformación ProteicaRESUMEN
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
Preclinical studies suggest that compounds with dual norepinephrine reuptake inhibitor (NRI) and 5-HT(1A) partial agonist properties may provide an important new therapeutic approach to ADHD, depression, and anxiety. Reported herein is the discovery of a novel chemical series with a favorable NRI and 5-HT(1A) partial agonist pharmacological profile as well as excellent selectivity for the norepinephrine transporter over the dopamine transporter.
Asunto(s)
Inhibidores de Captación Adrenérgica/síntesis química , Diseño de Fármacos , Proteínas de Transporte de Noradrenalina a través de la Membrana Plasmática/antagonistas & inhibidores , Piridinas/síntesis química , Agonistas del Receptor de Serotonina 5-HT1 , Agonistas de Receptores de Serotonina/síntesis química , Inhibidores de Captación Adrenérgica/metabolismo , Inhibidores de Captación Adrenérgica/farmacología , Línea Celular , Cristalografía por Rayos X , Evaluación Preclínica de Medicamentos/métodos , Humanos , Microsomas Hepáticos/efectos de los fármacos , Microsomas Hepáticos/metabolismo , Proteínas de Transporte de Noradrenalina a través de la Membrana Plasmática/metabolismo , Fenoles/síntesis química , Fenoles/metabolismo , Fenoles/farmacología , Piridinas/metabolismo , Piridinas/farmacología , Receptor de Serotonina 5-HT1A/metabolismo , Agonistas de Receptores de Serotonina/metabolismo , Agonistas de Receptores de Serotonina/farmacologíaRESUMEN
Synthesis, pharmacology, and pharmacokinetic profiles of (1R, 2S)-4-(2-cyano-cyclohexyl-oxy)-2-trifluoromethyl-benzonitrile are reported. This compound demonstrated remarkable potency for stimulating hair growth in a male C3H mouse model as well as reducing sebum production in the male Syrian hamster ear model.
Asunto(s)
Antagonistas de Andrógenos/farmacología , Cabello/crecimiento & desarrollo , Hidrocarburos Fluorados/farmacología , Nitrilos/farmacología , Sebo , Animales , Cricetinae , Hidrocarburos Fluorados/farmacocinética , Masculino , Mesocricetus , Ratones , Modelos Moleculares , Nitrilos/farmacocinéticaRESUMEN
A novel series of conformationally-restricted oxazolidinones was synthesized which possess a fused pyrazole ring substituted with various alkyl, aryl and heteroaryl substituents. A number of analogs exhibited potent activity against both gram-positive and fastidious gram-negative organisms.
Asunto(s)
Antibacterianos/química , Antibacterianos/farmacología , Bacterias Gramnegativas/efectos de los fármacos , Bacterias Grampositivas/efectos de los fármacos , Oxazolidinonas/química , Oxazolidinonas/farmacología , Pirazoles/farmacología , Estructura Molecular , Pirazoles/química , Relación Estructura-ActividadRESUMEN
Novel 2,4-diaminopyrimidine-based small molecule renin inhibitors are disclosed. Through high throughput screening, parallel synthesis, X-ray crystallography, and structure based drug design, we have developed the first non-chiral, non-peptidic, small molecular template to possess moderate potency against renin. The designed compounds consist of a novel 6-ethyl-5-(1,2,3,4-tetrahydroquinolin-7-yl)pyrimidine-2,4-diamine ring system that exhibit moderate potency (IC(50): 91-650 nM) against renin while remaining 'Rule-of-five' compliant.
Asunto(s)
Química Farmacéutica/métodos , Pirimidinas/química , Renina/antagonistas & inhibidores , Animales , Cristalografía por Rayos X , Diseño de Fármacos , Concentración 50 Inhibidora , Modelos Químicos , Modelos Moleculares , Conformación Molecular , Pirimidinas/síntesis química , Pirimidinas/farmacología , Ratas , Ratas Sprague-Dawley , Relación Estructura-ActividadRESUMEN
We describe a novel class of benzocycloheptanone derived oxazolidinone antibacterial agents. The synthesis and antibacterial activities with structure variation is discussed.
Asunto(s)
Antibacterianos/síntesis química , Antibacterianos/farmacología , Benzocicloheptenos/síntesis química , Benzocicloheptenos/farmacología , Oxazolidinonas/síntesis química , Oxazolidinonas/farmacología , Antibacterianos/química , Benzocicloheptenos/química , Bacterias Gramnegativas/efectos de los fármacos , Bacterias Grampositivas/efectos de los fármacos , Pruebas de Sensibilidad Microbiana , Estructura Molecular , Oxazolidinonas/química , Relación Estructura-ActividadRESUMEN
Herein, we report on the identification of three potent glycine and related amino acid-based series of FXa inhibitors containing a neutral P1 chlorophenyl pharmacophore. A X-ray crystal structure has shown that constrained glycine derivatives with optimized N-substitution can greatly increase hydrophobic interactions in the FXa active site. Also, the substitution of a pyridone ring for a phenylsulfone ring in the P4 sidechain resulted in an inhibitor with enhanced oral bioavailability.
Asunto(s)
Inhibidores del Factor Xa , Factor Xa/química , Glicina/análogos & derivados , Glicina/química , Inhibidores de Serina Proteinasa/química , Cristalografía por Rayos X , Humanos , Estructura Molecular , Conformación ProteicaRESUMEN
The chemical synthesis of a series of new penam sulfone derivatives bearing a 2beta-substituted-oxyimino and -hydrazone substituents, their beta-lactamase inhibitory properties against selected enzymes representing class A and C beta-lactamases are reported. The oxime containing penam sulfones strongly inhibited the Escherichia coli TEM-1 and Klebsiella pneumoniae cefotaximase (CTX-1) enzymes, but moderately inhibited the Pseudomonas aeruginosa 46012 cephalosporinase; while the 2beta-substituted-hydrazone derivatives were generally less active against these enzymes. Furthermore, most of the inhibitors enhanced the antibacterial activities of piperacillin (PIP) and ceftazidime (CAZ) particularly against TEM-1 and CTX-1 producing bacterial strains.