RESUMO
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.
Assuntos
Compostos Azabicíclicos/química , Compostos Azabicíclicos/farmacologia , Proteínas de Ligação às Penicilinas/metabolismo , Inibidores de beta-Lactamases/química , Inibidores de beta-Lactamases/farmacologia , Cinética , Testes de Sensibilidade Microbiana , Conformação ProteicaRESUMO
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
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.
Assuntos
Inibidores da Captação Adrenérgica/síntese química , Desenho de Fármacos , Proteínas da Membrana Plasmática de Transporte de Norepinefrina/antagonistas & inibidores , Piridinas/síntese química , Agonistas do Receptor 5-HT1 de Serotonina , Agonistas do Receptor de Serotonina/síntese química , Inibidores da Captação Adrenérgica/metabolismo , Inibidores da Captação Adrenérgica/farmacologia , Linhagem Celular , Cristalografia por Raios X , Avaliação Pré-Clínica de Medicamentos/métodos , Humanos , Microssomos Hepáticos/efeitos dos fármacos , Microssomos Hepáticos/metabolismo , Proteínas da Membrana Plasmática de Transporte de Norepinefrina/metabolismo , Fenóis/síntese química , Fenóis/metabolismo , Fenóis/farmacologia , Piridinas/metabolismo , Piridinas/farmacologia , Receptor 5-HT1A de Serotonina/metabolismo , Agonistas do Receptor de Serotonina/metabolismo , Agonistas do Receptor de Serotonina/farmacologiaRESUMO
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.
Assuntos
Antagonistas de Androgênios/farmacologia , Cabelo/crescimento & desenvolvimento , Hidrocarbonetos Fluorados/farmacologia , Nitrilas/farmacologia , Sebo , Animais , Cricetinae , Hidrocarbonetos Fluorados/farmacocinética , Masculino , Mesocricetus , Camundongos , Modelos Moleculares , Nitrilas/farmacocinéticaRESUMO
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.
Assuntos
Antibacterianos/química , Antibacterianos/farmacologia , Bactérias Gram-Negativas/efeitos dos fármacos , Bactérias Gram-Positivas/efeitos dos fármacos , Oxazolidinonas/química , Oxazolidinonas/farmacologia , Pirazóis/farmacologia , Estrutura Molecular , Pirazóis/química , Relação Estrutura-AtividadeRESUMO
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.
Assuntos
Química Farmacêutica/métodos , Pirimidinas/química , Renina/antagonistas & inibidores , Animais , Cristalografia por Raios X , Desenho de Fármacos , Concentração Inibidora 50 , Modelos Químicos , Modelos Moleculares , Conformação Molecular , Pirimidinas/síntese química , Pirimidinas/farmacologia , Ratos , Ratos Sprague-Dawley , Relação Estrutura-AtividadeRESUMO
We describe a novel class of benzocycloheptanone derived oxazolidinone antibacterial agents. The synthesis and antibacterial activities with structure variation is discussed.
Assuntos
Antibacterianos/síntese química , Antibacterianos/farmacologia , Benzocicloeptenos/síntese química , Benzocicloeptenos/farmacologia , Oxazolidinonas/síntese química , Oxazolidinonas/farmacologia , Antibacterianos/química , Benzocicloeptenos/química , Bactérias Gram-Negativas/efeitos dos fármacos , Bactérias Gram-Positivas/efeitos dos fármacos , Testes de Sensibilidade Microbiana , Estrutura Molecular , Oxazolidinonas/química , Relação Estrutura-AtividadeRESUMO
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.
Assuntos
Inibidores do Fator Xa , Fator Xa/química , Glicina/análogos & derivados , Glicina/química , Inibidores de Serina Proteinase/química , Cristalografia por Raios X , Humanos , Estrutura Molecular , Conformação ProteicaRESUMO
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.