RESUMEN
BACKGROUND: The prevalence of antibiotic resistance is increasing, and multidrug-resistant Pseudomonas aeruginosa has been identified as a serious threat to human health. The production of ß-lactamase is a key mechanism contributing to imipenem resistance in P. aeruginosa. Relebactam is a novel ß-lactamase inhibitor, active against class A and C ß-lactamases, that has been shown to restore imipenem susceptibility. In a series of studies, we assessed the interaction of relebactam with key mechanisms involved in carbapenem resistance in P. aeruginosa and to what extent relebactam might overcome imipenem non-susceptibility. RESULTS: Relebactam demonstrated no intrinsic antibacterial activity against P. aeruginosa, had no inoculum effect, and was not subject to efflux. Enzymology studies showed relebactam is a potent (overall inhibition constant: 27 nM), practically irreversible inhibitor of P. aeruginosa AmpC. Among P. aeruginosa clinical isolates from the SMART global surveillance program (2009, n = 993; 2011, n = 1702; 2015, n = 5953; 2016, n = 6165), imipenem susceptibility rates were 68.4% in 2009, 67.4% in 2011, 70.4% in 2015, and 67.3% in 2016. With the addition of 4 µg/mL relebactam, imipenem susceptibility rates increased to 87.6, 86.0, 91.7, and 89.8%, respectively. When all imipenem-non-susceptible isolates were pooled, the addition of 4 µg/mL relebactam reduced the mode imipenem minimum inhibitory concentration (MIC) 8-fold (from 16 µg/mL to 2 µg/mL) among all imipenem-non-susceptible isolates. Of 3747 imipenem-non-susceptible isolates that underwent molecular profiling, 1200 (32%) remained non-susceptible to the combination imipenem/relebactam (IMI/REL); 42% of these encoded class B metallo-ß-lactamases, 11% encoded a class A GES enzyme, and no class D enzymes were detected. No relationship was observed between alleles of the chromosomally-encoded P. aeruginosa AmpC and IMI/REL MIC. CONCLUSIONS: IMI/REL exhibited potential in the treatment of carbapenem-resistant P. aeruginosa infections, with the exception of isolates encoding class B, some GES alleles, and class D carbapenemases.
Asunto(s)
Compuestos de Azabiciclo/farmacología , Imipenem/farmacología , Pseudomonas aeruginosa/efectos de los fármacos , Antibacterianos/farmacología , Proteínas Bacterianas/efectos de los fármacos , Combinación de Medicamentos , Farmacorresistencia Bacteriana Múltiple/efectos de los fármacos , Humanos , Cinética , Pruebas de Sensibilidad Microbiana , Infecciones por Pseudomonas/microbiología , Pseudomonas aeruginosa/enzimología , beta-Lactamasas/efectos de los fármacosRESUMEN
Resistance to existing classes of antibiotics drives the need for discovery of novel compounds with unique mechanisms of action. Nargenicin A1, a natural product with limited antibacterial spectrum, was rediscovered in a whole-cell antisense assay. Macromolecular labeling in both Staphylococcus aureus and an Escherichia coli tolC efflux mutant revealed selective inhibition of DNA replication not due to gyrase or topoisomerase IV inhibition. S. aureus nargenicin-resistant mutants were selected at a frequency of â¼1 × 10(-9), and whole-genome resequencing found a single base-pair change in the dnaE gene, a homolog of the E. coli holoenzyme α subunit. A DnaE single-enzyme assay was exquisitely sensitive to inhibition by nargenicin, and other in vitro characterization studies corroborated DnaE as the target. Medicinal chemistry efforts may expand the spectrum of this novel mechanism antibiotic.
Asunto(s)
ADN Polimerasa III/genética , Descubrimiento de Drogas , Antibacterianos/química , Antibacterianos/metabolismo , Antibacterianos/farmacología , Replicación del ADN/efectos de los fármacos , ADN Polimerasa Dirigida por ADN/metabolismo , Farmacorresistencia Bacteriana/genética , Escherichia coli/efectos de los fármacos , Concentración 50 Inhibidora , Lactonas/química , Lactonas/metabolismo , Lactonas/farmacología , Mutación , Inhibidores de la Síntesis del Ácido Nucleico/química , Inhibidores de la Síntesis del Ácido Nucleico/farmacología , Staphylococcus aureus/efectos de los fármacosRESUMEN
ß-Lactamase inhibitors with a bicyclic urea core and a variety of heterocyclic side chains were prepared and evaluated as potential partners for combination with imipenem to overcome class A and C ß-lactamase mediated antibiotic resistance. The piperidine analog 3 (MK-7655) inhibited both class A and C ß-lactamases in vitro. It effectively restored imipenem's activity against imipenem-resistant Pseudomonas and Klebsiella strains at clinically achievable concentrations. A combination of MK-7655 and Primaxin® is currently in phase II clinical trials for the treatment of Gram-negative bacterial infections.
Asunto(s)
Compuestos de Azabiciclo/química , Compuestos de Azabiciclo/farmacología , Cilastatina/química , Descubrimiento de Drogas , Inhibidores Enzimáticos/química , Imipenem/química , Inhibidores de beta-Lactamasas , Cilastatina/farmacología , Combinación Cilastatina e Imipenem , Cristalografía por Rayos X , Combinación de Medicamentos , Farmacorresistencia Bacteriana/efectos de los fármacos , Imipenem/farmacología , Concentración 50 Inhibidora , Klebsiella/efectos de los fármacos , Pruebas de Sensibilidad Microbiana , Modelos Biológicos , Pseudomonas/efectos de los fármacos , Relación Estructura-ActividadRESUMEN
G-protein coupled receptor (GPCR) GPR109a is a molecular target for nicotinic acid and is expressed in adipocytes, spleen, and immune cells. Nicotinic acid has long been used for the treatment of dyslipidemia due to its capacity to positively affect serum lipids to a greater extent than other currently marketed drugs. We report a series of tricyclic pyrazole carboxylic acids that are potent and selective agonists of GPR109a. Compound R,R-19a (MK-1903) was advanced through preclinical studies, was well tolerated, and presented no apparent safety concerns. Compound R,R-19a was advanced into a phase 1 clinical trial and produced a robust decrease in plasma free fatty acids. On the basis of these results, R,R-19a was evaluated in a phase 2 study in humans. Because R,R-19a produced only a weak effect on serum lipids as compared with niacin, we conclude that the beneficial effects of niacin are most likely the result of an undefined GPR109a independent pathway.
Asunto(s)
Ácidos Grasos no Esterificados/sangre , Pirazoles/uso terapéutico , Receptores Acoplados a Proteínas G/agonistas , Animales , Humanos , Hipolipemiantes/farmacocinética , Hipolipemiantes/uso terapéutico , Masculino , Niacina/farmacología , Pirazoles/síntesis química , Pirazoles/farmacocinética , Ratas , Receptores Acoplados a Proteínas G/efectos de los fármacos , Receptores Nicotínicos/efectos de los fármacos , Estereoisomerismo , Vasodilatadores/farmacologíaRESUMEN
SAR studies of the substitution effect on the central phenyl ring of the biphenyl scaffold were carried out using anacetrapib (9a) as the benchmark. The results revealed that the new analogs with substitutions to replace trifluoromethyl (9a) had a significant impact on CETP inhibition in vitro. In fact, analogs with some small groups were as potent or more potent than the CF(3) derivative for CETP inhibition. Five of these new analogs raised HDL-C significantly (>20mg/dL). None of them however was better than anacetrapib in vivo. The synthesis and biological evaluation of these CETP inhibitors are described.
Asunto(s)
Proteínas de Transferencia de Ésteres de Colesterol/antagonistas & inhibidores , Oxazolidinonas/farmacología , Animales , Química Farmacéutica/métodos , HDL-Colesterol/metabolismo , Relación Dosis-Respuesta a Droga , Diseño de Fármacos , Humanos , Concentración 50 Inhibidora , Ratones , Ratones Transgénicos , Modelos Químicos , Relación Estructura-ActividadRESUMEN
The bridged monobactam ß-lactamase inhibitor MK-8712 (1) effectively inhibits class C ß-lactamases. Side chain N-alkylated and ring-opened analogs of 1 were prepared and evaluated for combination with imipenem to overcome class C ß-lactamase mediated resistance. Although some analogs were more potent inhibitors of AmpC, none exhibited better synergy with imipenem than 1.
Asunto(s)
Antibacterianos/química , Inhibidores Enzimáticos/química , Monobactamas/síntesis química , Inhibidores de beta-Lactamasas , Antibacterianos/síntesis química , Antibacterianos/farmacología , Sitios de Unión , Simulación por Computador , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/farmacología , Imipenem/farmacología , Pruebas de Sensibilidad Microbiana , Monobactamas/farmacología , Estructura Terciaria de Proteína , Relación Estructura-Actividad , beta-Lactamasas/metabolismoRESUMEN
The development of the structure-activity studies leading to the discovery of anacetrapib is described. These studies focused on varying the substitution of the oxazolidinone ring of the 5-aryloxazolidinone system. Specifically, it was found that substitution of the 4-position with a methyl group with the cis-stereochemistry relative to the 5-aryl group afforded compounds with increased cholesteryl ester transfer protein (CETP) inhibition potency and a robust in vivo effect on increasing HDL-C levels in transgenic mice expressing cynomolgus monkey CETP.
Asunto(s)
Proteínas de Transferencia de Ésteres de Colesterol/antagonistas & inhibidores , Oxazolidinonas/síntesis química , Animales , Proteínas de Transferencia de Ésteres de Colesterol/química , HDL-Colesterol/sangre , Humanos , Macaca fascicularis , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Oxazolidinonas/farmacocinética , Oxazolidinonas/farmacología , Proteínas Recombinantes/química , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
The preparation and characterization of a series of thiophenyl oxime phosphonate beta-lactamase inhibitors is described. A number of these analogs were potent and selective inhibitors of class C beta-lactamases from Pseudomonas aeruginosa and Enterobacter cloacae. Compounds 3b and 7 reduced the MIC of imipenem against an AmpC expressing strain of imipenem-resistant P. aeruginosa. A number of the title compounds retained micromolar potency against the class D OXA-40 beta-lactamase from Acinetobacter baumannii and at high concentrations compound 3b was shown to reduce the MIC of imipenem against a highly imipenem-resistant strain of A. baumanii expressing the OXA-40 beta-lactamase. In mice compound 3b exhibited phamacokinetics similar to imipenem.
Asunto(s)
Acinetobacter baumannii/efectos de los fármacos , Antibacterianos/química , Inhibidores Enzimáticos/química , Organofosfonatos/química , Oximas/química , Pseudomonas aeruginosa/efectos de los fármacos , Inhibidores de beta-Lactamasas , Antibacterianos/síntesis química , Antibacterianos/farmacología , Farmacorresistencia Bacteriana , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/farmacología , Imipenem/farmacología , Pruebas de Sensibilidad Microbiana , Organofosfonatos/síntesis química , Organofosfonatos/farmacología , Oximas/síntesis química , Oximas/farmacología , Tiofenos/química , beta-Lactamasas/metabolismoRESUMEN
The development of 2-phenylbenzoxazoles as inhibitors of cholesteryl ester transfer protein (CETP) is described. Initial efforts aimed at engineering replacements for the aniline substructures in the benchmark molecule. Reversing the connectivity of the central aniline lead to a new class of 2-(4-carbonylphenyl)benzoxazoles. Structure-activity studies at the C-7 and terminal pyridine ring allowed for the optimization of potency and HDLc-raising efficacy in this new class of inhibitors. These efforts lead to the discovery of benzoxazole 11v, which raised HDLc by 24 mg/dl in our transgenic mouse PD model.
Asunto(s)
Benzoxazoles/química , Benzoxazoles/farmacología , Proteínas de Transferencia de Ésteres de Colesterol/antagonistas & inhibidores , HDL-Colesterol/sangre , Animales , Diseño de Fármacos , Ratones , Ratones Transgénicos , Relación Estructura-ActividadRESUMEN
We describe structure-activity studies leading to the discovery of 2-arylbenzoxazole 3, the first in a series to raise serum high-density lipoprotein cholesterol levels in transgenic mice. Replacement of the 4-piperidinyloxy moiety with piperazinyl provided a more synthetically tractable lead, which upon optimization resulted in compound 4, an excellent inhibitor of cholesteryl ester transfer protein function with good pharmacokinetic properties and in vivo efficacy.
Asunto(s)
Acetanilidas/química , Benzoxazoles/química , Proteínas de Transferencia de Ésteres de Colesterol/antagonistas & inhibidores , HDL-Colesterol/sangre , Acetanilidas/síntesis química , Acetanilidas/farmacocinética , Animales , Benzoxazoles/síntesis química , Benzoxazoles/farmacocinética , Proteínas de Transferencia de Ésteres de Colesterol/metabolismo , Ratones , Ratones Transgénicos , Relación Estructura-ActividadRESUMEN
Recently, there has been a strong interest in the ability to increase levels of high density lipoprotein-cholesterol (HDL-C). This interest stems from the hypothesis that such an elevation in HDL-C will decrease the likelihood of cardiovascular disease. Inhibition of cholesteryl ester transfer protein (CETP) has been shown to elevate HDL-C levels in human subjects. This letter describes the discovery of a novel and potent (<100 nM IC50 for the inhibition of CE transfer) CETP inhibitor scaffold containing an oxazolidinone core.
RESUMEN
A new class of CETP inhibitors was designed and prepared. These compounds are potent both in vitro and in vivo. The most active compound (12d) has shown an ability to raise HDL significantly in transgenic mouse PD model.
Asunto(s)
Bencilaminas/química , Compuestos de Bifenilo/química , Carbamatos/química , Proteínas de Transferencia de Ésteres de Colesterol/antagonistas & inhibidores , Animales , Bencilaminas/síntesis química , Bencilaminas/farmacología , Compuestos de Bifenilo/síntesis química , Compuestos de Bifenilo/farmacología , Carbamatos/síntesis química , Carbamatos/farmacología , Proteínas de Transferencia de Ésteres de Colesterol/metabolismo , Modelos Animales de Enfermedad , Diseño de Fármacos , Lipoproteínas HDL/metabolismo , Ratones , Ratones Transgénicos , Relación Estructura-ActividadRESUMEN
A series of pyrazolyl propionyl cyclohexenamides were discovered as full agonists for the high affinity niacin receptor GPR109A. The structure-activity relationship (SAR) studies were aimed to improve activity on GPR109A, reduce Cytochrome P450 2C8 (CYP2C8) and Cytochrome P450 2C9 (CYP2C9) inhibition, reduce serum shift and improve pharmacokinetic (PK) profiles.
Asunto(s)
Amidas/química , Ciclohexenos/farmacología , Receptores Acoplados a Proteínas G/agonistas , Animales , Ciclohexenos/química , Ciclohexenos/farmacocinética , Ratones , Ratas , Receptores Nicotínicos , Relación Estructura-ActividadRESUMEN
Biaryl cyclohexene carboxylic acids were discovered as full and potent niacin receptor (GPR109A) agonists. Compound 1e (MK-6892) displayed excellent receptor activity, good PK across species, remarkably clean off-target profiles, good ancillary pharmacology, and superior therapeutic window over niacin regarding the FFA reduction versus vasodilation in rats and dogs.
Asunto(s)
Ácidos Carboxílicos/farmacología , Ácidos Ciclohexanocarboxílicos/farmacología , Ciclohexenos/química , Descubrimiento de Drogas , Oxadiazoles/farmacología , Receptores Acoplados a Proteínas G/agonistas , Animales , Área Bajo la Curva , Unión Competitiva , Células CHO , Ácidos Carboxílicos/química , Ácidos Carboxílicos/farmacocinética , Cricetinae , Cricetulus , Ácidos Ciclohexanocarboxílicos/química , Ácidos Ciclohexanocarboxílicos/farmacocinética , Perros , Evaluación Preclínica de Medicamentos , Ácidos Grasos no Esterificados/sangre , Humanos , Tasa de Depuración Metabólica , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Modelos Químicos , Estructura Molecular , Oxadiazoles/química , Oxadiazoles/farmacocinética , Ratas , Receptores Acoplados a Proteínas G/genética , Receptores Acoplados a Proteínas G/metabolismo , Receptores Nicotínicos/genética , Receptores Nicotínicos/metabolismo , Relación Estructura-Actividad , Vasodilatación/efectos de los fármacosRESUMEN
Bridged monobactam beta-lactamase inhibitors were prepared and evaluated as potential partners for combination with imipenem to overcome class C beta-lactamase mediated resistance. The (S)-azepine analog 2 was found to be effective in both in vitro and in vivo assays and was selected for preclinical development.
Asunto(s)
Carbapenémicos/química , Descubrimiento de Drogas/métodos , Imipenem/química , Inhibidores de beta-Lactamasas , Animales , Compuestos Bicíclicos Heterocíclicos con Puentes/química , Compuestos Bicíclicos Heterocíclicos con Puentes/farmacología , Carbapenémicos/farmacología , Combinación de Medicamentos , Imipenem/farmacología , Ratones , Infecciones por Pseudomonas/tratamiento farmacológico , Infecciones por Pseudomonas/enzimología , Pseudomonas aeruginosa/efectos de los fármacos , Pseudomonas aeruginosa/fisiología , Relación Estructura-Actividad , Resistencia betalactámica/efectos de los fármacos , Resistencia betalactámica/fisiología , beta-Lactamasas/metabolismoRESUMEN
The development of a series of 2-arylbenzoxazole alpha-alkoxyamide and beta-alkoxyamine inhibitors of cholesteryl ester transfer protein (CETP) is described. Highly fluorinated alpha-alkoxyamides proved to be potent inhibitors of CETP in vitro, and the highly fluorinated 2-arylbenzoxazole beta-alkoxyamine 4 showed a desirable combination of in vitro potency (IC(50)=151 nM) and oral bioavailability in the mouse.
Asunto(s)
Benzoxazoles/síntesis química , Benzoxazoles/metabolismo , Proteínas de Transferencia de Ésteres de Colesterol/antagonistas & inhibidores , Proteínas de Transferencia de Ésteres de Colesterol/metabolismo , Alcoholes/síntesis química , Alcoholes/metabolismo , Amidas/síntesis química , Amidas/metabolismoRESUMEN
A series of 2-arylbenzoxazole inhibitors of the cholesterol ester transfer protein (CETP) is described. Structure-activity studies focused on variation of the substitution of the benzoxazole moiety. Substitution at the 5- and 7-positions of the benzoxazole moiety was found to be beneficial for CETP inhibition. Compound 47 was found to be the most potent inhibitor in this series and inhibited CETP with an IC(50) of 28nM.
Asunto(s)
Acetanilidas/química , Anticolesterolemiantes/química , Benzoxazoles/química , Proteínas de Transferencia de Ésteres de Colesterol/antagonistas & inhibidores , Acetanilidas/síntesis química , Acetanilidas/farmacocinética , Administración Oral , Animales , Anticolesterolemiantes/síntesis química , Anticolesterolemiantes/farmacocinética , Benzoxazoles/síntesis química , Benzoxazoles/farmacocinética , Proteínas de Transferencia de Ésteres de Colesterol/metabolismo , Ratones , Relación Estructura-ActividadRESUMEN
Tricyclic analogues were rationally designed as the high affinity niacin receptor G-protein-coupled receptor 109A (GPR109A) agonists by overlapping three lead structures. Various tricyclic anthranilide and cycloalkene carboxylic acid full agonists were discovered with excellent in vitro activity. Compound 2g displayed a good therapeutic index regarding free fatty acids (FFA) reduction and vasodilation effects in rats, with very weak cytochrome P450 2C8 (CYP2C8) and cytochrome P450 2C9 (CYP2C9) inhibition, and a good mouse pharmacokinetics (PK) profile.
Asunto(s)
Cicloparafinas/síntesis química , Rubor/inducido químicamente , Compuestos Heterocíclicos con 3 Anillos/síntesis química , Hipolipemiantes/síntesis química , Niacina/metabolismo , Receptores Acoplados a Proteínas G/agonistas , ortoaminobenzoatos/síntesis química , Adipocitos/efectos de los fármacos , Adipocitos/metabolismo , Animales , Células CHO , Cricetinae , Cricetulus , Cicloparafinas/efectos adversos , Cicloparafinas/farmacología , Oído/irrigación sanguínea , Compuestos Heterocíclicos con 3 Anillos/efectos adversos , Compuestos Heterocíclicos con 3 Anillos/farmacología , Humanos , Hipolipemiantes/efectos adversos , Hipolipemiantes/farmacología , Técnicas In Vitro , Lipólisis , Masculino , Ratones , Ensayo de Unión Radioligante , Ratas , Receptores Nicotínicos , Relación Estructura-Actividad , Vasodilatación/efectos de los fármacos , ortoaminobenzoatos/efectos adversos , ortoaminobenzoatos/farmacologíaRESUMEN
Platensimycin (1) displays antibacterial activity due to its inhibition of the elongation condensing enzyme (FabF), a novel mode of action that could potentially lead to a breakthrough in developing a new generation of antibiotics. The medicinal chemistry efforts were focused on the modification of the enone moiety of platensimycin and several analogs showed significant activity against FabF and possess antibacterial activity.
Asunto(s)
3-Oxoacil-(Proteína Transportadora de Acil) Sintasa/antagonistas & inhibidores , Adamantano/síntesis química , Aminobenzoatos/síntesis química , Anilidas/síntesis química , Antibacterianos/síntesis química , Proteínas Bacterianas/antagonistas & inhibidores , Química Farmacéutica/métodos , 3-Oxoacil-(Proteína Transportadora de Acil) Sintasa/química , Adamantano/farmacología , Aminobenzoatos/farmacología , Anilidas/farmacología , Antibacterianos/farmacología , Proteínas Bacterianas/química , Cristalografía por Rayos X/métodos , Diseño de Fármacos , Farmacorresistencia Microbiana , Enterococcus faecalis/metabolismo , Concentración 50 Inhibidora , Meticilina/farmacología , Pruebas de Sensibilidad Microbiana , Modelos Químicos , Estructura Molecular , Streptomyces/metabolismo , Relación Estructura-ActividadRESUMEN
Pyrazolopyrimidines were discovered as the first class of allosteric agonists for the high affinity nicotinic acid receptor GPR109A. In addition to its intrinsic activity, compound 9n significantly enhances nicotinic acid binding to the receptor, thereby potentiating the functional efficacy of nicotinic acid.