RESUMEN
Novel (non-fluoroquinolone) inhibitors of bacterial type II topoisomerases (NBTIs) are an emerging class of antibacterial agents. We report an optimized series of cyclobutylaryl-substituted NBTIs. Compound 14 demonstrated excellent activity both in vitro (S. aureus MIC90=0.125µg/mL) and in vivo (systemic and tissue infections). Enhanced inhibition of Topoisomerase IV correlated with improved activity in S. aureus strains with mutations conferring resistance to NBTIs. Compound 14 also displayed an improved hERG IC50 of 85.9µM and a favorable profile in the anesthetized guinea pig model.
Asunto(s)
Antibacterianos/farmacología , Girasa de ADN/metabolismo , Topoisomerasa de ADN IV/antagonistas & inhibidores , Quinolinas/farmacología , Inhibidores de Topoisomerasa II/farmacología , Inhibidores de Topoisomerasa/farmacología , Animales , Antibacterianos/síntesis química , Antibacterianos/química , Topoisomerasa de ADN IV/metabolismo , Relación Dosis-Respuesta a Droga , Canales de Potasio Éter-A-Go-Go/metabolismo , Cobayas , Humanos , Pruebas de Sensibilidad Microbiana , Estructura Molecular , Quinolinas/síntesis química , Quinolinas/química , Staphylococcus aureus/efectos de los fármacos , Staphylococcus aureus/enzimología , Streptococcus pyogenes/efectos de los fármacos , Streptococcus pyogenes/enzimología , Relación Estructura-Actividad , Inhibidores de Topoisomerasa II/síntesis química , Inhibidores de Topoisomerasa II/química , Inhibidores de Topoisomerasa/síntesis química , Inhibidores de Topoisomerasa/químicaRESUMEN
A structurally novel set of inhibitors of bacterial type II topoisomerases with potent in vitro and in vivo antibacterial activity was developed. Dual-targeting ability, hERG inhibition, and pharmacokinetic properties were also assessed.
Asunto(s)
Antibacterianos/farmacología , Topoisomerasa de ADN IV/antagonistas & inhibidores , Inhibidores Enzimáticos/farmacología , Quinolinas/farmacología , Staphylococcus aureus/efectos de los fármacos , Streptococcus pneumoniae/efectos de los fármacos , Inhibidores de Topoisomerasa II , Animales , Antibacterianos/administración & dosificación , Antibacterianos/química , Girasa de ADN/metabolismo , Topoisomerasa de ADN IV/metabolismo , ADN-Topoisomerasas de Tipo II/metabolismo , Relación Dosis-Respuesta a Droga , Inhibidores Enzimáticos/administración & dosificación , Inhibidores Enzimáticos/química , Canales de Potasio Éter-A-Go-Go/antagonistas & inhibidores , Humanos , Pruebas de Sensibilidad Microbiana , Estructura Molecular , Quinolinas/administración & dosificación , Quinolinas/química , Ratas , Staphylococcus aureus/enzimología , Streptococcus pneumoniae/enzimología , Relación Estructura-ActividadRESUMEN
Murine models of infection were used to study the effect of linezolid on the virulence of Gram-negative bacteria and to assess potential pharmacodynamic interactions with ciprofloxacin in the treatment of these infections, prompted by observations from a recent clinical trial. Naive and immunosuppressed mice were challenged with Klebsiella pneumoniae 53A1109, K. pneumoniae GC6658, and Pseudomonas aeruginosa UC12120 in acute sepsis and pulmonary infection models, using different serial dilutions of these pathogens (groups of 8 animals each). Linezolid (100 mg/kg/dose) was administered orally at 0.5 and 4.0 h postchallenge in the sepsis model and at 4 h postchallenge followed by 2 days of twice-daily treatment in the pulmonary model. Further, ciprofloxacin alone and in combination with oral linezolid was investigated in the sepsis model. Survival was assessed for 4 and 10 days postchallenge in the systemic and respiratory models, respectively. The data were fitted to a nonlinear regression analysis to determine 50% lethal doses (LD(50)s) and 50% protective doses (PD(50)s). A clinically relevant, high-dose regimen of linezolid had no significant effect on LD(50) in these models. This lack of effect was independent of immune status. A combination of oral ciprofloxacin with linezolid yielded lower PD(50)s than oral ciprofloxacin alone (ciprofloxacin in combination, 8.4 to 32.7 mg/kg; oral ciprofloxacin, 39.4 to 88.3 mg/kg). Linezolid did not improve the efficacy of subcutaneous ciprofloxacin (ciprofloxacin in combination, 2.0 to 2.4 mg/kg; subcutaneous ciprofloxacin, 2.0 to 2.8 mg/kg). In conclusion, linezolid does not seem to potentiate infections caused by Gram-negative pathogens or to interact antagonistically with ciprofloxacin.
Asunto(s)
Acetamidas/administración & dosificación , Antibacterianos/administración & dosificación , Ciprofloxacina/administración & dosificación , Infecciones por Klebsiella/tratamiento farmacológico , Oxazolidinonas/administración & dosificación , Infecciones por Pseudomonas/tratamiento farmacológico , Sepsis/tratamiento farmacológico , Animales , Vías de Administración de Medicamentos , Esquema de Medicación , Interacciones Farmacológicas , Femenino , Huésped Inmunocomprometido , Infecciones por Klebsiella/inmunología , Infecciones por Klebsiella/microbiología , Infecciones por Klebsiella/mortalidad , Klebsiella pneumoniae/efectos de los fármacos , Klebsiella pneumoniae/crecimiento & desarrollo , Dosificación Letal Mediana , Linezolid , Ratones , Modelos Animales , Infecciones por Pseudomonas/inmunología , Infecciones por Pseudomonas/microbiología , Infecciones por Pseudomonas/mortalidad , Pseudomonas aeruginosa/efectos de los fármacos , Pseudomonas aeruginosa/crecimiento & desarrollo , Sepsis/inmunología , Sepsis/microbiología , Sepsis/mortalidad , Tasa de Supervivencia , Resultado del TratamientoRESUMEN
Novel siderophore-linked monobactams with in vitro and in vivo anti-microbial activity against MDR Gram-negative pathogens are described.
Asunto(s)
Farmacorresistencia Bacteriana Múltiple/efectos de los fármacos , Bacterias Gramnegativas/efectos de los fármacos , Infecciones por Bacterias Gramnegativas/tratamiento farmacológico , Monobactamas/farmacología , Animales , Sitios de Unión/efectos de los fármacos , Proteínas Sanguíneas/química , Cristalografía por Rayos X , Relación Dosis-Respuesta a Droga , Infecciones por Bacterias Gramnegativas/microbiología , Humanos , Ratones , Pruebas de Sensibilidad Microbiana , Modelos Moleculares , Estructura Molecular , Monobactamas/síntesis química , Monobactamas/química , Ratas , Relación Estructura-ActividadRESUMEN
Evidence of emerging Plasmodium falciparum resistance to artemisinin-based combination therapies, documented in western Cambodia, underscores the continuing need to identify new antimalarial combinations. Given recent reports of the resurgence of chloroquine-sensitive P. falciparum parasites in Malawi, after the enforced and prolonged withdrawal of this drug, and indications of a possible synergistic interaction with the macrolide azithromycin, we sought to further characterize chloroquine-azithromycin combinations for their in vitro and in vivo antimalarial properties. In vitro 96-h susceptibility testing of chloroquine-azithromycin combinations showed mostly additive interactions against freshly cultured P. falciparum field isolates obtained from Mali. Some evidence of synergy, however, was apparent at the fractional 90% inhibitory concentration level. Additional in vitro testing highlighted the resistance reversal properties of amlodipine for both chloroquine and quinine. In vivo experiments, using the Peters 4-day suppressive test in a P. yoelii mouse model, revealed up to 99.9% suppression of parasitemia following treatment with chloroquine-azithromycin plus the R enantiomer of amlodipine. This enantiomer was chosen because it does not manifest the cardiac toxicities observed with the racemic mixture. Pharmacokinetic/pharmacodynamic analyses in this rodent model and subsequent extrapolation to a 65-kg adult led to the estimation that 1.8 g daily of R-amlodipine would be required to achieve similar efficacy in humans, for whom this is likely an unsafe dose. While these data discount amlodipine as an additional partner for chloroquine-based combination therapy, our studies continue to support azithromycin as a safe and effective addition to antimalarial combination therapies.
Asunto(s)
Amlodipino/farmacología , Antimaláricos/farmacología , Azitromicina/farmacología , Cloroquina/farmacología , Animales , Interacciones Farmacológicas , Femenino , Ratones , Pruebas de Sensibilidad Parasitaria , Plasmodium falciparum/efectos de los fármacosRESUMEN
Explorations in the pyrimidinetrione series of MMP-13 inhibitors led to the discovery of a series of spiro-fused compounds that are potent and selective inhibitors of MMP-13. While other spiro-fused motifs are hydrolytically unstable, presumably due to electronic destabilization of the pyrimidinetrione ring, the spiropyrrolidine series does not share this liability. Greater than 100-fold selectivity versus other MMP family members was achieved by incorporation of an extended aryl-heteroaryl P1'group. When dosed as the sodium salt, these compounds displayed excellent oral absorption and pharmacokinetic properties. Despite the selectivity, a representative of this series produced fibroplasia in a 14 day rat study.
Asunto(s)
Inhibidores de la Metaloproteinasa de la Matriz , Inhibidores de Proteasas/química , Pirimidinas/química , Pirrolidinas/química , Compuestos de Espiro/química , Animales , Estabilidad de Enzimas/efectos de los fármacos , Metaloproteinasa 13 de la Matriz/metabolismo , Inhibidores de Proteasas/farmacología , Pirimidinas/farmacología , Pirrolidinas/farmacología , Ratas , Compuestos de Espiro/farmacología , Relación Estructura-ActividadRESUMEN
We report novel polymyxin analogues with improved antibacterial in vitro potency against polymyxin resistant recent clinical isolates of Acinetobacter baumannii and Pseudomonas aeruginosa . In addition, a human renal cell in vitro assay (hRPTEC) was used to inform structure-toxicity relationships and further differentiate analogues. Replacement of the Dab-3 residue with a Dap-3 in combination with a relatively polar 6-oxo-1-phenyl-1,6-dihydropyridine-3-carbonyl side chain as a fatty acyl replacement yielded analogue 5x, which demonstrated an improved in vitro antimicrobial and renal cytotoxicity profiles relative to polymyxin B (PMB). However, in vivo PK/PD comparison of 5x and PMB in a murine neutropenic thigh model against P. aeruginosa strains with matched MICs showed that 5x was inferior to PMB in vivo, suggesting a lack of improved therapeutic index in spite of apparent in vitro advantages.
Asunto(s)
Infección Hospitalaria/tratamiento farmacológico , Descubrimiento de Drogas , Resistencia a Múltiples Medicamentos/efectos de los fármacos , Bacterias Gramnegativas/efectos de los fármacos , Polimixinas/química , Polimixinas/farmacología , beta-Alanina/análogos & derivados , Animales , Antibacterianos/química , Antibacterianos/farmacocinética , Antibacterianos/farmacología , Antibacterianos/toxicidad , Perros , Femenino , Bacterias Gramnegativas/fisiología , Humanos , Masculino , Pruebas de Sensibilidad Microbiana , Polimixinas/farmacocinética , Polimixinas/toxicidad , Ratas , beta-Alanina/químicaRESUMEN
Herein we describe the structure-aided design and synthesis of a series of pyridone-conjugated monobactam analogues with in vitro antibacterial activity against clinically relevant Gram-negative species including Pseudomonas aeruginosa , Klebsiella pneumoniae , and Escherichia coli . Rat pharmacokinetic studies with compound 17 demonstrate low clearance and low plasma protein binding. In addition, evidence is provided for a number of analogues suggesting that the siderophore receptors PiuA and PirA play a role in drug uptake in P. aeruginosa strain PAO1.
Asunto(s)
Antibacterianos/farmacología , Bacterias Gramnegativas/efectos de los fármacos , Monobactamas/farmacología , Piridonas/farmacología , Animales , Antibacterianos/química , Antibacterianos/farmacocinética , Escherichia coli/efectos de los fármacos , Concentración 50 Inhibidora , Klebsiella pneumoniae/efectos de los fármacos , Masculino , Pruebas de Sensibilidad Microbiana , Estructura Molecular , Monobactamas/química , Monobactamas/farmacocinética , Pseudomonas aeruginosa/efectos de los fármacos , Piridonas/química , Piridonas/farmacocinética , Ratas , Ratas WistarRESUMEN
We investigated the effects of the matrix metalloproteinase 13 (MMP13)-selective inhibitor, 5-(4-{4-[4-(4-fluorophenyl)-1,3-oxazol-2-yl]phenoxy}phenoxy)-5-(2-methoxyethyl) pyrimidine-2,4,6(1H,3H,5H)-trione (Cmpd-1), on the primary tumor growth and breast cancer-associated bone remodeling using xenograft and syngeneic mouse models. We used human breast cancer MDA-MB-231 cells inoculated into the mammary fat pad and left ventricle of BALB/c Nu/Nu mice, respectively, and spontaneously metastasizing 4T1.2-Luc mouse mammary cells inoculated into mammary fat pad of BALB/c mice. In a prevention setting, treatment with Cmpd-1 markedly delayed the growth of primary tumors in both models, and reduced the onset and severity of osteolytic lesions in the MDA-MB-231 intracardiac model. Intervention treatment with Cmpd-1 on established MDA-MB-231 primary tumors also significantly inhibited subsequent growth. In contrast, no effects of Cmpd-1 were observed on soft organ metastatic burden following intracardiac or mammary fat pad inoculations of MDA-MB-231 and 4T1.2-Luc cells respectively. MMP13 immunostaining of clinical primary breast tumors and experimental mice tumors revealed intra-tumoral and stromal expression in most tumors, and vasculature expression in all. MMP13 was also detected in osteoblasts in clinical samples of breast-to-bone metastases. The data suggest that MMP13-selective inhibitors, which lack musculoskeletal side effects, may have therapeutic potential both in primary breast cancer and cancer-induced bone osteolysis.
Asunto(s)
Neoplasias de la Mama/complicaciones , Neoplasias de la Mama/patología , Inhibidores de la Metaloproteinasa de la Matriz , Osteólisis/etiología , Osteólisis/patología , Inhibidores de Proteasas/farmacología , Animales , Neoplasias Óseas/patología , Neoplasias Óseas/secundario , Neoplasias de la Mama/enzimología , Neoplasias de la Mama/prevención & control , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Creatina Quinasa/metabolismo , Modelos Animales de Enfermedad , Células Endoteliales/efectos de los fármacos , Células Endoteliales/metabolismo , Femenino , Técnica del Anticuerpo Fluorescente , Humanos , Metaloproteinasa 13 de la Matriz/metabolismo , Ratones , Osteoblastos/efectos de los fármacos , Osteoblastos/enzimología , Osteoblastos/patología , Osteólisis/enzimología , Inhibidores de Proteasas/sangre , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
A novel series of monocarbam compounds exhibiting promising antibacterial activity against multidrug resistant Gram-negative microorganisms is reported, along with the synthesis of one such molecule MC-1 (1). Also reported are structure-activity relationships associated with the in vitro and in vivo efficacy of 1 and related analogues in addition to the hydrolytic stability of such compounds and possible implications thereof.
RESUMEN
Respiratory tract bacterial strains are becoming increasingly resistant to currently marketed macrolide antibiotics. The current alternative telithromycin (1) from the newer ketolide class of macrolides addresses resistance but is hampered by serious safety concerns, hepatotoxicity in particular. We have discovered a novel series of azetidinyl ketolides that focus on mitigation of hepatotoxicity by minimizing hepatic turnover and time-dependent inactivation of CYP3A isoforms in the liver without compromising the potency and efficacy of 1.
Asunto(s)
Azetidinas/química , Resistencia a Múltiples Medicamentos/efectos de los fármacos , Cetólidos/química , Cetólidos/farmacología , Infecciones del Sistema Respiratorio/tratamiento farmacológico , Animales , Bacterias/efectos de los fármacos , Infecciones Comunitarias Adquiridas/tratamiento farmacológico , Susceptibilidad a Enfermedades , Descubrimiento de Drogas , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos , Humanos , Cetólidos/efectos adversos , Cetólidos/síntesis química , Cetólidos/uso terapéutico , Ratones , Pruebas de Sensibilidad MicrobianaRESUMEN
Using SAR from two related series of pyrimidinetrione-based inhibitors, compounds with potent MMP-13 inhibition and >100-fold selectivity against other MMPs have been identified. Despite high molecular weights, clogPs, and polar surface areas, the compounds are generally well absorbed and have excellent pharmacokinetic (PK) properties when dosed as sodium salts. In a rat fibrosis model, a compound from the series displayed no fibrosis at exposures many fold greater than its MMP-13 IC50.
Asunto(s)
Inhibidores de la Metaloproteinasa de la Matriz , Inhibidores de Proteasas/síntesis química , Inhibidores de Proteasas/farmacología , Pirimidinonas/química , Animales , Fibrosis/tratamiento farmacológico , Fibrosis/patología , Ácidos Hidroxámicos/química , Concentración 50 Inhibidora , Peso Molecular , Ratas , Sales (Química)/química , Sodio/química , Relación Estructura-ActividadRESUMEN
A series of pipecolic hydroxamate inhibitors of MMP-13 and aggrecanase was discovered based on screening known inhibitors of TNF-alpha converting enzyme (TACE). Potency versus aggrecanase was optimized by modification of the benzyloxyarylsulfonamide group. Incorporation of geminal alkyl substitution at the 3-position of the piperidine ring improved metabolic stability, presumably by increasing steric hindrance around the metabolically labile hydroxamic acid. This modification also resulted in dramatic improvement of aggrecanase activity with a slight reduction in selectivity versus MMP-1. Synthesis, structure activity relationships, and strategies to reduce metabolic clearance are described.
Asunto(s)
Endopeptidasas/efectos de los fármacos , Ácidos Hidroxámicos/farmacología , Inhibidores de la Metaloproteinasa de la Matriz , Inhibidores de Proteasas/farmacología , Ácidos Hidroxámicos/química , Metaloproteinasa 13 de la Matriz , Inhibidores de Proteasas/químicaRESUMEN
Through the use of computational modeling, a series of pyrimidinetrione-based inhibitors of MMP-13 was designed based on a lead inhibitor identified through file screening. Incorporation of a biaryl ether moiety at the C-5 position of the pyrimidinetrione ring resulted in a dramatic enhancement of MMP-13 potency. Protein crystallography revealed that this moiety binds in the S(1)(') pocket of the enzyme. Optimization of the C-4 substituent of the terminal aromatic ring led to incorporation of selectivity versus MMP-14 (MT-1 MMP). Structure activity relationships of the biaryl ether substituent are presented as is pharmacokinetic data for a compound that meets our in vitro potency and selectivity goals.
Asunto(s)
Inhibidores Enzimáticos/síntesis química , Inhibidores de la Metaloproteinasa de la Matriz , Pirimidinas/química , Sitios de Unión , Colagenasas/química , Cristalografía por Rayos X , Inhibidores Enzimáticos/farmacología , Metaloproteinasa 13 de la Matriz , Relación Estructura-ActividadRESUMEN
A series of novel MMP-13 and TNF-alpha converting enzyme inhibitors based on piperazine 2-hydroxamic acid scaffolds are described. The TACE, MMP-1 and MMP-13 activity of these inhibitors as well as the effect of substitution of the piperazine nitrogen and the P-1' benzyloxy tailpiece is discussed. Moderate in vivo activity is observed with several members of this group.