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1.
J Med Chem ; 67(5): 3400-3418, 2024 Mar 14.
Artículo en Inglés | MEDLINE | ID: mdl-38387069

RESUMEN

The use of ß-lactam (BL) and ß-lactamase inhibitor combination to overcome BL antibiotic resistance has been validated through clinically approved drug products. However, unmet medical needs still exist for the treatment of infections caused by Gram-negative (GN) bacteria expressing metallo-ß-lactamases. Previously, we reported our effort to discover pan inhibitors of three main families in this class: IMP, VIM, and NDM. Herein, we describe our work to improve the GN coverage spectrum in combination with imipenem and relebactam. This was achieved through structure- and property-based optimization to tackle the GN cell penetration and efflux challenges. A significant discovery was made that inhibition of both VIM alleles, VIM-1 and VIM-2, is essential for broad GN coverage, especially against VIM-producing P. aeruginosa. In addition, pharmacokinetics and nonclinical safety profiles were investigated for select compounds. Key findings from this drug discovery campaign laid the foundation for further lead optimization toward identification of preclinical candidates.


Asunto(s)
Antibacterianos , Inhibidores de beta-Lactamasas , Humanos , Inhibidores de beta-Lactamasas/farmacología , Inhibidores de beta-Lactamasas/uso terapéutico , Inhibidores de beta-Lactamasas/química , Antibacterianos/química , Imipenem/farmacología , beta-Lactamasas , Bacterias Gramnegativas , Pruebas de Sensibilidad Microbiana
2.
J Med Chem ; 65(24): 16234-16251, 2022 12 22.
Artículo en Inglés | MEDLINE | ID: mdl-36475645

RESUMEN

With the emergence and rapid spreading of NDM-1 and existence of clinically relevant VIM-1 and IMP-1, discovery of pan inhibitors targeting metallo-beta-lactamases (MBLs) became critical in our battle against bacterial infection. Concurrent with our fragment and high-throughput screenings, we performed a knowledge-based search of known metallo-beta-lactamase inhibitors (MBLIs) to identify starting points for early engagement of medicinal chemistry. A class of compounds exemplified by 11, discovered earlier as B. fragilis metallo-beta-lactamase inhibitors, was selected for in silico virtual screening. From these efforts, compound 12 was identified with activity against NDM-1 only. Initial exploration on metal binding design followed by structure-guided optimization led to the discovery of a series of compounds represented by 23 with a pan MBL inhibition profile. In in vivo studies, compound 23 in combination with imipenem (IPM) robustly lowered the bacterial burden in a murine infection model and became the lead for the invention of MBLI clinical candidates.


Asunto(s)
Infecciones Bacterianas , Inhibidores de beta-Lactamasas , Animales , Ratones , Inhibidores de beta-Lactamasas/farmacología , Inhibidores de beta-Lactamasas/uso terapéutico , Inhibidores de beta-Lactamasas/química , Imipenem/farmacología , Imipenem/uso terapéutico , beta-Lactamasas/metabolismo , Antibacterianos/farmacología , Antibacterianos/uso terapéutico , Antibacterianos/química , Pruebas de Sensibilidad Microbiana
3.
Bioorg Med Chem Lett ; 30(17): 127390, 2020 09 01.
Artículo en Inglés | MEDLINE | ID: mdl-32738973

RESUMEN

Bruton's tyrosine kinase (BTK) is a Tec family kinase with a well-defined role in the B cell receptor (BCR) pathway. It has become an attractive kinase target for selective B cell inhibition, and for the treatment of B cell related diseases. Many BTK inhibitors have been discovered for the treatment of cancer and rheumatoid arthritis, including a series of BTK inhibitors based on 8-amino-imidazo[1,5-a]pyrazine we recently reported. The X-ray crystal structures of BTK with inhibitors were also published, which provided great help for the SAR design. Here we report our SAR work introducing ring constraints for the 3-position piperidine amides on the BTK inhibitors based on 8-amino-imidazo[1,5-a]pyrazine. This modification improved the potency in BTK inhibitions, as well as the PK profile and the off-target selectivity. The dose-dependent efficacy of two BTK inhibitors was observed in the rat collagen induced arthritis (CIA) model.


Asunto(s)
Agammaglobulinemia Tirosina Quinasa/antagonistas & inhibidores , Imidazoles/química , Inhibidores de Proteínas Quinasas/química , Pirazinas/química , Agammaglobulinemia Tirosina Quinasa/metabolismo , Animales , Artritis Experimental/tratamiento farmacológico , Sitios de Unión , Compuestos Bicíclicos con Puentes/química , Cristalografía por Rayos X , Modelos Animales de Enfermedad , Perros , Relación Dosis-Respuesta a Droga , Semivida , Humanos , Imidazoles/metabolismo , Imidazoles/uso terapéutico , Simulación de Dinámica Molecular , Inhibidores de Proteínas Quinasas/metabolismo , Inhibidores de Proteínas Quinasas/uso terapéutico , Pirazinas/metabolismo , Pirazinas/uso terapéutico , Ratas , Ratas Wistar , Relación Estructura-Actividad , Familia-src Quinasas/antagonistas & inhibidores , Familia-src Quinasas/metabolismo
4.
ACS Med Chem Lett ; 9(7): 679-684, 2018 Jul 12.
Artículo en Inglés | MEDLINE | ID: mdl-30034600

RESUMEN

A novel series of tricyclic tetrahydroquinolines were identified as potent and selective CRTh2 receptor antagonists. The agonism and antagonism switch was achieved through structure-based drug design (SBDD) using a CRTh2 receptor homologue model. The challenge of very low exposures in pharmacokinetic studies was overcome by exhaustive medicinal chemistry lead optimization through focused SAR studies on the tricyclic core. Further optimization resulted in the identification of the preclinical candidate 4-(cyclopropyl((3aS,9R,9aR)-7-fluoro-4-(4-(trifluoromethoxy)benzoyl)-2,3,3a,4,9,9a-hexahydro-1H-cyclopenta[b]quinolin-9-yl)amino)-4-oxobutanoic acid (15c, MK-8318) with potent and selective CRTh2 antagonist activity and a favorable PK profile suitable for once daily oral dosing for potential treatment of asthma.

5.
Proc Natl Acad Sci U S A ; 115(28): E6614-E6621, 2018 07 10.
Artículo en Inglés | MEDLINE | ID: mdl-29941590

RESUMEN

The outer membrane (OM) of Gram-negative bacteria forms a robust permeability barrier that blocks entry of toxins and antibiotics. Most OM proteins (OMPs) assume a ß-barrel fold, and some form aqueous channels for nutrient uptake and efflux of intracellular toxins. The Bam machine catalyzes rapid folding and assembly of OMPs. Fidelity of OMP biogenesis is monitored by the σE stress response. When OMP folding defects arise, the proteases DegS and RseP act sequentially to liberate σE into the cytosol, enabling it to activate transcription of the stress regulon. Here, we identify batimastat as a selective inhibitor of RseP that causes a lethal decrease in σE activity in Escherichia coli, and we further identify RseP mutants that are insensitive to inhibition and confer resistance. Remarkably, batimastat treatment allows the capture of elusive intermediates in the OMP biogenesis pathway and offers opportunities to better understand the underlying basis for σE essentiality.


Asunto(s)
Proteínas de la Membrana Bacteriana Externa , Endopeptidasas , Proteínas de Escherichia coli , Escherichia coli , Proteínas de la Membrana , Desplegamiento Proteico , Factores de Transcripción , Proteínas de la Membrana Bacteriana Externa/genética , Proteínas de la Membrana Bacteriana Externa/metabolismo , Endopeptidasas/genética , Endopeptidasas/metabolismo , Escherichia coli/genética , Escherichia coli/metabolismo , Proteínas de Escherichia coli/genética , Proteínas de Escherichia coli/metabolismo , Proteínas de la Membrana/genética , Proteínas de la Membrana/metabolismo , Factores de Transcripción/metabolismo
6.
Bioorg Med Chem Lett ; 27(23): 5344-5348, 2017 12 01.
Artículo en Inglés | MEDLINE | ID: mdl-29110986

RESUMEN

New synthetic methods were developed for the preparation of 2,3,6-trisubstituted 1-oxo-1,2-dihydroisoquinolines as CRTh2 antagonists. The isoquinolinone core could be constructed before the introduction of substitution groups or synthesized through a catalytic intramolecular cyclization reaction with desired substitution groups properly installed. These synthetic strategies have helped to accelerate the SAR development of this series, and potent lead compounds were identified in both the CRTh2 receptor binding assay and the CD11b biomarker assay.


Asunto(s)
Isoquinolinas/farmacología , Receptores Inmunológicos/antagonistas & inhibidores , Receptores de Prostaglandina/antagonistas & inhibidores , Relación Dosis-Respuesta a Droga , Humanos , Isoquinolinas/síntesis química , Isoquinolinas/química , Estructura Molecular , Relación Estructura-Actividad
7.
ACS Chem Biol ; 12(9): 2448-2456, 2017 09 15.
Artículo en Inglés | MEDLINE | ID: mdl-28806050

RESUMEN

Though phenotypic and target-based high-throughput screening approaches have been employed to discover new antibiotics, the identification of promising therapeutic candidates remains challenging. Each approach provides different information, and understanding their results can provide hypotheses for a mechanism of action (MoA) and reveal actionable chemical matter. Here, we describe a framework for identifying efficacy targets of bioactive compounds. High throughput biophysical profiling against a broad range of targets coupled with machine learning was employed to identify chemical features with predicted efficacy targets for a given phenotypic screen. We validate the approach on data from a set of 55 000 compounds in 24 historical internal antibacterial phenotypic screens and 636 bacterial targets screened in high-throughput biophysical binding assays. Models were built to reveal the relationships between phenotype, target, and chemotype, which recapitulated mechanisms for known antibacterials. We also prospectively identified novel inhibitors of dihydrofolate reductase with nanomolar antibacterial efficacy against Mycobacterium tuberculosis. Molecular modeling provided structural insight into target-ligand interactions underlying selective killing activity toward mycobacteria over human cells.


Asunto(s)
Antituberculosos/química , Antituberculosos/farmacología , Antagonistas del Ácido Fólico/química , Antagonistas del Ácido Fólico/farmacología , Mycobacterium tuberculosis/efectos de los fármacos , Mycobacterium tuberculosis/enzimología , Tetrahidrofolato Deshidrogenasa/metabolismo , Evaluación Preclínica de Medicamentos , Células HeLa , Ensayos Analíticos de Alto Rendimiento , Humanos , Ligandos , Simulación del Acoplamiento Molecular , Mycobacterium tuberculosis/crecimiento & desarrollo , Tuberculosis/tratamiento farmacológico , Tuberculosis/microbiología
8.
PLoS One ; 12(7): e0180965, 2017.
Artículo en Inglés | MEDLINE | ID: mdl-28700746

RESUMEN

To combat the threat of antibiotic-resistant Gram-negative bacteria, novel agents that circumvent established resistance mechanisms are urgently needed. Our approach was to focus first on identifying bioactive small molecules followed by chemical lead prioritization and target identification. Within this annotated library of bioactives, we identified a small molecule with activity against efflux-deficient Escherichia coli and other sensitized Gram-negatives. Further studies suggested that this compound inhibited DNA replication and selection for resistance identified mutations in a subunit of E. coli DNA gyrase, a type II topoisomerase. Our initial compound demonstrated weak inhibition of DNA gyrase activity while optimized compounds demonstrated significantly improved inhibition of E. coli and Pseudomonas aeruginosa DNA gyrase and caused cleaved complex stabilization, a hallmark of certain bactericidal DNA gyrase inhibitors. Amino acid substitutions conferring resistance to this new class of DNA gyrase inhibitors reside exclusively in the TOPRIM domain of GyrB and are not associated with resistance to the fluoroquinolones, suggesting a novel binding site for a gyrase inhibitor.


Asunto(s)
Antibacterianos/farmacología , Girasa de ADN/metabolismo , Inhibidores de Topoisomerasa II/farmacología , Farmacorresistencia Bacteriana/genética , Escherichia coli/efectos de los fármacos , Escherichia coli/enzimología , Fluoroquinolonas/farmacología , Pruebas de Sensibilidad Microbiana , Dominios Proteicos , Pseudomonas aeruginosa/efectos de los fármacos , Pseudomonas aeruginosa/enzimología
9.
Bioorg Med Chem Lett ; 27(16): 3939-3943, 2017 08 15.
Artículo en Inglés | MEDLINE | ID: mdl-28720503

RESUMEN

8-Amino-imidazo[1,5-a]pyrazine-based Bruton's tyrosine kinase (BTK) inhibitors, such as 6, exhibited potent inhibition of BTK but required improvements in both kinase and hERG selectivity (Liu et al., 2016; Gao et al., 2017). In an effort to maintain the inhibitory activity of these analogs and improve their selectivity profiles, we carried out SAR exploration of groups at the 3-position of pyrazine compound 6. This effort led to the discovery of the morpholine group as an optimized pharmacophore. Compounds 13, 23 and 38 displayed excellent BTK potencies, kinase and hERG selectivities, and pharmacokinetic profiles.


Asunto(s)
Artritis Reumatoide/tratamiento farmacológico , Descubrimiento de Drogas , Imidazoles/farmacología , Morfolinas/farmacología , Inhibidores de Proteínas Quinasas/farmacología , Proteínas Tirosina Quinasas/antagonistas & inhibidores , Artritis Reumatoide/metabolismo , Relación Dosis-Respuesta a Droga , Humanos , Imidazoles/síntesis química , Imidazoles/química , Leucocitos Mononucleares/efectos de los fármacos , Leucocitos Mononucleares/metabolismo , Modelos Moleculares , Estructura Molecular , Morfolinas/síntesis química , Morfolinas/química , Inhibidores de Proteínas Quinasas/síntesis química , Inhibidores de Proteínas Quinasas/química , Proteínas Tirosina Quinasas/metabolismo , Relación Estructura-Actividad , Regulador Transcripcional ERG/antagonistas & inhibidores , Regulador Transcripcional ERG/metabolismo
10.
J Med Chem ; 60(9): 3851-3865, 2017 05 11.
Artículo en Inglés | MEDLINE | ID: mdl-28322556

RESUMEN

We describe our optimization efforts to improve the physicochemical properties, solubility, and off-target profile of 1, an inhibitor of TarO, an early stage enzyme in the biosynthetic pathway for wall teichoic acid (WTA) synthesis. Compound 1 displayed a TarO IC50 of 125 nM in an enzyme assay and possessed very high lipophilicity (clogP = 7.1) with no measurable solubility in PBS buffer. Structure-activity relationship (SAR) studies resulted in a series of compounds with improved lipophilic ligand efficiency (LLE) consistent with the reduction of clogP. From these efforts, analog 9 was selected for our initial in vivo study, which in combination with subefficacious dose of imipenem (IPM) robustly lowered the bacterial burden in a neutropenic Staphylococci murine infection model. Concurrent with our in vivo optimization effort using 9, we further improved LLE as exemplified by a much more druglike analog 26.


Asunto(s)
Lípidos/química , Bibliotecas de Moléculas Pequeñas , Animales , Femenino , Staphylococcus aureus Resistente a Meticilina/efectos de los fármacos , Staphylococcus aureus Resistente a Meticilina/crecimiento & desarrollo , Ratones , Ratones Endogámicos BALB C , Pruebas de Sensibilidad Microbiana , Solubilidad , Relación Estructura-Actividad
11.
Bioorg Med Chem Lett ; 27(6): 1471-1477, 2017 03 15.
Artículo en Inglés | MEDLINE | ID: mdl-28254166

RESUMEN

We report the design and synthesis of a series of novel Bruton's Tyrosine Kinase (BTK) inhibitors with a carboxylic acid moiety in the ribose pocket. This series of compounds has demonstrated much improved off-target selectivities including adenosine uptake (AdU) inhibition compared to the piperidine amide series. Optimization of the initial lead compound 4 based on BTK enzyme inhibition, and human peripheral blood mononuclear cell (hPBMC) and human whole blood (hWB) activity led to the discovery of compound 40, with potent BTK inhibition, reduced off target activities, as well as favorable pharmacokinetic profile in both rat and dog.


Asunto(s)
Ácidos Carboxílicos/farmacología , Descubrimiento de Drogas , Inhibidores de Proteínas Quinasas/farmacología , Proteínas Tirosina Quinasas/antagonistas & inhibidores , Agammaglobulinemia Tirosina Quinasa , Animales , Humanos , Ratas
12.
Bioorg Med Chem Lett ; 26(17): 4250-5, 2016 09 01.
Artículo en Inglés | MEDLINE | ID: mdl-27476420

RESUMEN

IRAK4 has been identified as potential therapeutic target for inflammatory and autoimmune diseases. Herein we report the identification and initial SAR studies of a new class of pyrazole containing IRAK4 inhibitors designed to expand chemical diversity and improve off target activity of a previously identified series. These compounds maintain potent IRAK4 activity and desirable ligand efficiency. Rat clearance and a variety of off target activities were also examined, resulting in encouraging data with tractable SAR.


Asunto(s)
Quinasas Asociadas a Receptores de Interleucina-1/antagonistas & inhibidores , Inhibidores de Proteínas Quinasas/química , Pirazoles/química , Animales , Sitios de Unión , Cristalografía por Rayos X , Semivida , Humanos , Quinasas Asociadas a Receptores de Interleucina-1/metabolismo , Ligandos , Simulación de Dinámica Molecular , Unión Proteica , Inhibidores de Proteínas Quinasas/metabolismo , Inhibidores de Proteínas Quinasas/farmacocinética , Estructura Terciaria de Proteína , Pirazoles/metabolismo , Pirazoles/farmacocinética , Ratas , Relación Estructura-Actividad
13.
Bioorg Med Chem Lett ; 26(19): 4743-4747, 2016 10 01.
Artículo en Inglés | MEDLINE | ID: mdl-27575474

RESUMEN

A series of benzimidazole analogs have been synthesized to improve the profile of the previous lead compounds tarocin B and 1. The syntheses, structure-activity relationships, and selected biochemical data of these analogs are described. The optimization efforts allowed the identification of 21, a fluoro-substituted benzimidazole, exhibiting potent TarO inhibitory activity and typical profile for a wall teichoic acid (WTA) biosynthesis inhibitor. Compound 21 displayed a potent synergistic and bactericidal effect in combination with imipenem against diverse methicillin-resistant Staphylococci.


Asunto(s)
Antibacterianos/farmacología , Bencimidazoles/farmacología , Staphylococcus aureus Resistente a Meticilina/efectos de los fármacos , Ácidos Teicoicos/antagonistas & inhibidores , Animales , Antibacterianos/química , Bencimidazoles/química , Pruebas de Sensibilidad Microbiana , Ratas , Relación Estructura-Actividad , Ácidos Teicoicos/biosíntesis
14.
Bioorg Med Chem Lett ; 26(16): 3999-4002, 2016 08 15.
Artículo en Inglés | MEDLINE | ID: mdl-27436582

RESUMEN

The widespread emergence of methicillin-resistant Staphylococcus aureus (MRSA) has dramatically eroded the efficacy of current ß-lactam antibiotics and created an urgent need for novel treatment options. Using an S. aureus phenotypic screening strategy, we have identified small molecule early stage wall teichoic acid (WTA) pathway-specific inhibitors predicted to be chemically synergistic with ß-lactams. These previously disclosed inhibitors, termed tarocins, demonstrate by genetic and biochemical means inhibition of TarO, the first step in WTA biosynthesis. Tarocins demonstrate potent bactericidal synergy in combination with broad spectrum ß-lactam antibiotics across diverse clinical isolates of methicillin-resistant Staphylococci. The synthesis and structure-activity relationships (SAR) of a tarocin series will be detailed. Tarocins and other WTA inhibitors may provide a rational strategy to develop Gram-positive bactericidal ß-lactam combination agents active against methicillin-resistant Staphylococci.


Asunto(s)
Antibacterianos/química , Ácidos Teicoicos/metabolismo , beta-Lactamas/antagonistas & inhibidores , Antibacterianos/síntesis química , Antibacterianos/farmacología , Pared Celular/efectos de los fármacos , Pared Celular/metabolismo , Evaluación Preclínica de Medicamentos , Staphylococcus aureus Resistente a Meticilina/efectos de los fármacos , Pruebas de Sensibilidad Microbiana , Staphylococcus aureus/efectos de los fármacos , Relación Estructura-Actividad , beta-Lactamas/metabolismo
15.
Antimicrob Agents Chemother ; 60(8): 4830-9, 2016 08.
Artículo en Inglés | MEDLINE | ID: mdl-27246784

RESUMEN

Oxabicyclooctane-linked novel bacterial topoisomerase inhibitors (NBTIs) represent a new class of recently described antibacterial agents with broad-spectrum activity. NBTIs dually inhibit the clinically validated bacterial targets DNA gyrase and topoisomerase IV and have been shown to bind distinctly from known classes of antibacterial agents directed against these targets. Herein we report the molecular, cellular, and in vivo characterization of AM-8722 as a representative N-alkylated-1,5-naphthyridone left-hand-side-substituted NBTI. Consistent with its mode of action, macromolecular labeling studies revealed a specific effect of AM-8722 to dose dependently inhibit bacterial DNA synthesis. AM-8722 displayed greater intrinsic enzymatic potency than levofloxacin versus both DNA gyrase and topoisomerase IV from Staphylococcus aureus and Escherichia coli and displayed selectivity against human topoisomerase II. AM-8722 was rapidly bactericidal and exhibited whole-cell activity versus a range of Gram-negative and Gram-positive organisms, with no whole-cell potency shift due to the presence of DNA or human serum. Frequency-of-resistance studies demonstrated an acceptable rate of resistance emergence in vitro at concentrations 16- to 32-fold the MIC. AM-8722 displayed acceptable pharmacokinetic properties and was shown to be efficacious in mouse models of bacterial septicemia. Overall, AM-8722 is a selective and potent NBTI that displays broad-spectrum antimicrobial activity in vitro and in vivo.


Asunto(s)
Antibacterianos/farmacología , Ciclooctanos/farmacología , Girasa de ADN/metabolismo , Topoisomerasa de ADN IV/antagonistas & inhibidores , ADN-Topoisomerasas de Tipo II/metabolismo , Inhibidores de Topoisomerasa II/farmacología , Animales , Línea Celular , ADN Bacteriano/genética , Perros , Escherichia coli/efectos de los fármacos , Escherichia coli/genética , Infecciones por Escherichia coli/tratamiento farmacológico , Humanos , Ratones , Pruebas de Sensibilidad Microbiana , Ratas , Ratas Wistar , Infecciones Estafilocócicas/tratamiento farmacológico , Staphylococcus aureus/efectos de los fármacos , Staphylococcus aureus/genética
16.
ACS Med Chem Lett ; 7(2): 198-203, 2016 Feb 11.
Artículo en Inglés | MEDLINE | ID: mdl-26985298

RESUMEN

Bruton's tyrosine kinase (BTK) is a Tec family kinase with a well-defined role in the B cell receptor (BCR) pathway. It has become an attractive kinase target for selective B cell inhibition and for the treatment of B cell related diseases. We report a series of compounds based on 8-amino-imidazo[1,5-a]pyrazine that are potent reversible BTK inhibitors with excellent kinase selectivity. Selectivity is achieved through specific interactions of the ligand with the kinase hinge and driven by aminopyridine hydrogen bondings with Ser538 and Asp539, and by hydrophobic interaction of trifluoropyridine in the back pocket. These interactions are evident in the X-ray crystal structure of the lead compounds 1 and 3 in the complex with the BTK enzyme. Our lead compounds show desirable PK profiles and efficacy in the preclinical rat collagen induced arthritis model.

17.
Sci Transl Med ; 8(329): 329ra32, 2016 Mar 09.
Artículo en Inglés | MEDLINE | ID: mdl-26962156

RESUMEN

The widespread emergence of methicillin-resistant Staphylococcus aureus (MRSA) has dramatically eroded the efficacy of current ß-lactam antibiotics and created an urgent need for new treatment options. We report an S. aureus phenotypic screening strategy involving chemical suppression of the growth inhibitory consequences of depleting late-stage wall teichoic acid biosynthesis. This enabled us to identify early-stage pathway-specific inhibitors of wall teichoic acid biosynthesis predicted to be chemically synergistic with ß-lactams. We demonstrated by genetic and biochemical means that each of the new chemical series discovered, herein named tarocin A and tarocin B, inhibited the first step in wall teichoic acid biosynthesis (TarO). Tarocins do not have intrinsic bioactivity but rather demonstrated potent bactericidal synergy in combination with broad-spectrum ß-lactam antibiotics against diverse clinical isolates of methicillin-resistant staphylococci as well as robust efficacy in a murine infection model of MRSA. Tarocins and other inhibitors of wall teichoic acid biosynthesis may provide a rational strategy to develop Gram-positive bactericidal ß-lactam combination agents active against methicillin-resistant staphylococci.


Asunto(s)
Proteínas Bacterianas/metabolismo , Vías Biosintéticas/efectos de los fármacos , Pared Celular/metabolismo , Staphylococcus aureus Resistente a Meticilina/efectos de los fármacos , Ácidos Teicoicos/biosíntesis , beta-Lactamas/farmacología , Animales , Pared Celular/efectos de los fármacos , Dicloxacilina/farmacología , Dicloxacilina/uso terapéutico , Femenino , Ratones Endogámicos BALB C , Pruebas de Sensibilidad Microbiana , Modelos Moleculares , Fenotipo , Infecciones Estafilocócicas/tratamiento farmacológico , Infecciones Estafilocócicas/microbiología , Resultado del Tratamiento
18.
Nature ; 526(7575): 672-7, 2015 Oct 29.
Artículo en Inglés | MEDLINE | ID: mdl-26416753

RESUMEN

Riboswitches are non-coding RNA structures located in messenger RNAs that bind endogenous ligands, such as a specific metabolite or ion, to regulate gene expression. As such, riboswitches serve as a novel, yet largely unexploited, class of emerging drug targets. Demonstrating this potential, however, has proven difficult and is restricted to structurally similar antimetabolites and semi-synthetic analogues of their cognate ligand, thus greatly restricting the chemical space and selectivity sought for such inhibitors. Here we report the discovery and characterization of ribocil, a highly selective chemical modulator of bacterial riboflavin riboswitches, which was identified in a phenotypic screen and acts as a structurally distinct synthetic mimic of the natural ligand, flavin mononucleotide, to repress riboswitch-mediated ribB gene expression and inhibit bacterial cell growth. Our findings indicate that non-coding RNA structural elements may be more broadly targeted by synthetic small molecules than previously expected.


Asunto(s)
Pirimidinas/química , Pirimidinas/farmacología , ARN Bacteriano/química , ARN Bacteriano/efectos de los fármacos , Riboswitch/efectos de los fármacos , Animales , Aptámeros de Nucleótidos/química , Bacterias/citología , Bacterias/efectos de los fármacos , Bacterias/crecimiento & desarrollo , Secuencia de Bases , Cristalografía por Rayos X , Infecciones por Escherichia coli/tratamiento farmacológico , Infecciones por Escherichia coli/microbiología , Proteínas de Escherichia coli/genética , Femenino , Mononucleótido de Flavina/metabolismo , Regulación Bacteriana de la Expresión Génica/efectos de los fármacos , Proteínas de Choque Térmico/genética , Transferasas Intramoleculares/genética , Ligandos , Ratones , Ratones Endogámicos DBA , Modelos Moleculares , Datos de Secuencia Molecular , Pirimidinas/aislamiento & purificación , Pirimidinas/uso terapéutico , ARN Bacteriano/genética , Reproducibilidad de los Resultados , Riboflavina/biosíntesis , Riboswitch/genética , Especificidad por Sustrato
19.
ACS Med Chem Lett ; 6(8): 942-7, 2015 Aug 13.
Artículo en Inglés | MEDLINE | ID: mdl-26288698

RESUMEN

We report the identification and synthesis of a series of aminopyrimidin-4-one IRAK4 inhibitors. Through high throughput screening, an aminopyrimidine hit was identified and modified via structure enabled design to generate a new, potent, and kinase selective pyrimidin-4-one chemotype. This chemotype is exemplified by compound 16, which has potent IRAK4 inhibition activity (IC50 = 27 nM) and excellent kinase selectivity (>100-fold against 99% of 111 tested kinases), and compound 31, which displays potent IRAK4 activity (IC50 = 93 nM) and good rat bioavailability (F = 42%).

20.
ACS Med Chem Lett ; 6(6): 677-82, 2015 Jun 11.
Artículo en Inglés | MEDLINE | ID: mdl-26101573

RESUMEN

IRAK4 is a critical upstream kinase in the IL-1R/TLR signaling pathway. Inhibition of IRAK4 is hypothesized to be beneficial in the treatment of autoimmune related disorders. A screening campaign identified a pyrazole class of IRAK4 inhibitors that were determined by X-ray crystallography to exhibit an unusual binding mode. SAR efforts focused on the identification of a potent and selective inhibitor with good aqueous solubility and rodent pharmacokinetics. Pyrazole C-3 piperidines were well tolerated, with N-sulfonyl analogues generally having good rodent oral exposure but poor solubility. N-Alkyl piperidines exhibited excellent solubility and reduced exposure. Pyrazoles possessing N-1 pyridine and fluorophenyl substituents were among the most active. Piperazine 32 was a potent enzyme inhibitor with good cellular activity. Compound 32 reduced the in vivo production of proinflammatory cytokines and was orally efficacious in a mouse antibody induced arthritis disease model of inflammation.

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