RESUMEN
The mammalian mitochondrial branched-chain ketoacid dehydrogenase (BCKD) complex is a multienzyme complex involved in the catabolism of branched-chain amino acids. BCKD is regulated by the BCKD kinase, or BCKDK, which binds to the E2 subunit of BCKD, phosphorylates its E1 subunit, and inhibits enzymatic activity. Inhibition of the BCKD complex results in increased levels of branched-chain amino acids and branched-chain ketoacids, and this buildup has been associated with heart failure, type 2 diabetes mellitus, and nonalcoholic fatty liver disease. To find BCKDK inhibitors for potential treatment of these diseases, we performed both NMR and virtual fragment screening and identified tetrazole-bearing fragments that bind BCKDK at multiple sites. Through structure-based virtual screening expanding from these fragments, the angiotensin receptor blocker class antihypertension drugs and angiotensin receptor blocker-like compounds were discovered to be potent BCKDK inhibitors, suggesting potential new avenues for heart failure treatment combining BCKDK inhibition and antihypertension.
Asunto(s)
3-Metil-2-Oxobutanoato Deshidrogenasa (Lipoamida) , Antagonistas de Receptores de Angiotensina , Humanos , 3-Metil-2-Oxobutanoato Deshidrogenasa (Lipoamida)/metabolismo , Aminoácidos de Cadena Ramificada/metabolismo , Antagonistas de Receptores de Angiotensina/farmacología , Complejos Multienzimáticos/metabolismo , Insuficiencia Cardíaca , HipertensiónRESUMEN
N-methyl-d-aspartate receptors (NMDARs) are glutamate-gated ion channels that play key roles in brain physiology and pathology. Because numerous pathologic conditions involve NMDAR overactivation, subunit-selective antagonists hold strong therapeutic potential, although clinical successes remain limited. Among the most promising NMDAR-targeting drugs are allosteric inhibitors of GluN2B-containing receptors. Since the discovery of ifenprodil, a range of GluN2B-selective compounds with strikingly different structural motifs have been identified. This molecular diversity raises the possibility of distinct binding sites, although supporting data are lacking. Using X-ray crystallography, we show that EVT-101, a GluN2B antagonist structurally unrelated to the classic phenylethanolamine pharmacophore, binds at the same GluN1/GluN2B dimer interface as ifenprodil but adopts a remarkably different binding mode involving a distinct subcavity and receptor interactions. Mutagenesis experiments demonstrate that this novel binding site is physiologically relevant. Moreover, in silico docking unveils that GluN2B-selective antagonists broadly divide into two distinct classes according to binding pose. These data widen the allosteric and pharmacological landscape of NMDARs and offer a renewed structural framework for designing next-generation GluN2B antagonists with therapeutic value for brain disorders.
Asunto(s)
Antagonistas Adrenérgicos alfa/metabolismo , Drogas en Investigación/metabolismo , Moduladores del Transporte de Membrana/metabolismo , Modelos Moleculares , Receptores de N-Metil-D-Aspartato/metabolismo , Antagonistas Adrenérgicos alfa/química , Antagonistas Adrenérgicos alfa/farmacología , Regulación Alostérica/efectos de los fármacos , Sustitución de Aminoácidos , Animales , Sitios de Unión , Biología Computacional , Drogas en Investigación/química , Drogas en Investigación/farmacología , Sistemas Especialistas , Humanos , Imidazoles/química , Imidazoles/metabolismo , Imidazoles/farmacología , Ligandos , Moduladores del Transporte de Membrana/química , Moduladores del Transporte de Membrana/farmacología , Conformación Molecular , Simulación del Acoplamiento Molecular , Mutación , Oxadiazoles/química , Oxadiazoles/metabolismo , Oxadiazoles/farmacología , Piperidinas/química , Piperidinas/metabolismo , Piperidinas/farmacología , Dominios y Motivos de Interacción de Proteínas , Subunidades de Proteína/antagonistas & inhibidores , Subunidades de Proteína/química , Subunidades de Proteína/genética , Subunidades de Proteína/metabolismo , Piridazinas/química , Piridazinas/metabolismo , Piridazinas/farmacología , Pirimidinas/química , Pirimidinas/metabolismo , Pirimidinas/farmacología , Receptores de N-Metil-D-Aspartato/antagonistas & inhibidores , Receptores de N-Metil-D-Aspartato/química , Receptores de N-Metil-D-Aspartato/genética , Proteínas Recombinantes de Fusión/química , Proteínas Recombinantes de Fusión/metabolismo , Proteínas de Xenopus/antagonistas & inhibidores , Proteínas de Xenopus/química , Proteínas de Xenopus/genética , Proteínas de Xenopus/metabolismoRESUMEN
In this paper, we disclose insights on the root causes of three structure-activity relationship (SAR) observations encountered in the discovery of the IRAK4 inhibitor Zimlovisertib (PF-06650833). The first is a nonlinear potency SAR encountered with the isoquinoline ether substituent, the second is a potency enhancement introduced by fluorine substitution on the lactam, and the third is a slight potency preference for all-syn (2S,3S,4S) stereochemistry in the fluorine-substituted lactam. We present new data that help to inform us of the origins of these unexpected SAR trends.
RESUMEN
Human glucokinase (GK) is a principal regulating sensor of plasma glucose levels. Mutations that inactivate GK are linked to diabetes, and mutations that activate it are associated with hypoglycemia. Unique kinetic properties equip GK for its regulatory role: although it has weak basal affinity for glucose, positive cooperativity in its binding of glucose causes a rapid increase in catalytic activity when plasma glucose concentrations rise above euglycemic levels. In clinical trials, small molecule GK activators (GKAs) have been efficacious in lowering plasma glucose and enhancing glucose-stimulated insulin secretion, but they carry a risk of overly activating GK and causing hypoglycemia. The theoretical models proposed to date attribute the positive cooperativity of GK to the existence of distinct protein conformations that interconvert slowly and exhibit different affinities for glucose. Here we report the respective crystal structures of the catalytic complex of GK and of a GK-glucose complex in a wide open conformation. To assess conformations of GK in solution, we also carried out small angle x-ray scattering experiments. The results showed that glucose dose-dependently converts GK from an apo conformation to an active open conformation. Compared with wild type GK, activating mutants required notably lower concentrations of glucose to be converted to the active open conformation. GKAs decreased the level of glucose required for GK activation, and different compounds demonstrated distinct activation profiles. These results lead us to propose a modified mnemonic model to explain cooperativity in GK. Our findings may offer new approaches for designing GKAs with reduced hypoglycemic risk.
Asunto(s)
Regulación de la Expresión Génica , Glucoquinasa/metabolismo , Glucosa/química , Sitio Alostérico , Catálisis , Activación Enzimática , Homeostasis , Humanos , Hipoglucemia/patología , Cinética , Modelos Biológicos , Modelos Moleculares , Mutación , Conformación Proteica , Dispersión de Radiación , Rayos XRESUMEN
Glucokinase activators are a class of experimental agents under investigation as a therapy for Type 2 diabetes mellitus. An X-ray crystal structure of a modestly potent agent revealed the potential to substitute the common heterocyclic amide donor-acceptor motif for a pyridone moiety. We have successfully demonstrated that both pyridone and pyrimidone heterocycles can be used as a potent donor-acceptor substituent. Several sub-micromolar analogs that possess the desired partial activator profile were synthesized and characterized. Unfortunately, the most potent activators suffered from sub-optimal pharmacokinetic properties. Nonetheless, these donor-acceptor motifs may find utility in other glucokinase activator series or beyond.
Asunto(s)
Activadores de Enzimas/química , Glucoquinasa/metabolismo , Pirimidinonas/síntesis química , Regulación Alostérica , Secuencias de Aminoácidos , Animales , Sitios de Unión , Modelos Moleculares , Pirimidinonas/química , RatasRESUMEN
Macrocyclic retinoic acid receptor-related orphan receptor C2 (RORC2) inverse agonists have been designed with favorable properties for topical administration. Inspired by the unanticipated bound conformation of an acyclic sulfonamide-based RORC2 ligand from cocrystal structure analysis, macrocyclic linker connections between the halves of the molecule were explored. Further optimization of analogues was accomplished to maximize potency and refine physiochemical properties (MW, lipophilicity) best suited for topical application. Compound 14 demonstrated potent inhibition of interleukin-17A (IL-17A) production by human Th17 cells and in vitro permeation through healthy human skin achieving high total compound concentration in both skin epidermis and dermis layers.
RESUMEN
Lipid A is an essential component of the Gram negative outer membrane, which protects the bacterium from attack of many antibiotics. The Lipid A biosynthesis pathway is essential for Gram negative bacterial growth and is unique to these bacteria. The first committed step in Lipid A biosynthesis is catalysis by LpxC, a zinc dependent deacetylase. We show the design of an LpxC inhibitor utilizing a robust model which directed efficient design of picomolar inhibitors. Analysis of physiochemical properties drove design to focus on an optimal lipophilicity profile. Further structure based design took advantage of a conserved water network over the active site, and with the optimal lipophilicity profile, led to an improved LpxC inhibitor with in vivo activity against wild type Pseudomonas aeruginosa.
Asunto(s)
Amidohidrolasas/química , Antibacterianos/síntesis química , Inhibidores Enzimáticos/síntesis química , Ácidos Hidroxámicos/síntesis química , Pseudomonas aeruginosa/efectos de los fármacos , Amidohidrolasas/antagonistas & inhibidores , Antibacterianos/farmacología , Dominio Catalítico , Diseño de Fármacos , Inhibidores Enzimáticos/farmacología , Interacciones Hidrofóbicas e Hidrofílicas , Ácidos Hidroxámicos/farmacología , Lípido A/metabolismo , Pruebas de Sensibilidad Microbiana , Modelos Moleculares , Unión Proteica , Pseudomonas aeruginosa/enzimología , Relación Estructura-Actividad , Agua/químicaRESUMEN
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
A diaryl ketone series was identified as vanin-1 inhibitors from a high-throughput screening campaign. While this novel scaffold provided valuable probe 2 that was used to build target confidence, concerns over the ketone moiety led to the replacement of this group. The successful replacement of this moiety was achieved with pyrimidine carboxamides derived from cyclic secondary amines that were extensively characterized using biophysical and crystallographic methods as competitive inhibitors of vanin-1. Through optimization of potency and physicochemical and ADME properties, and guided by co-crystal structures with vanin-1, 3 was identified with a suitable profile for advancement into preclinical development.
Asunto(s)
Amidohidrolasas/antagonistas & inhibidores , Piridinas/síntesis química , Piridinas/farmacología , Animales , Colitis/inducido químicamente , Colitis/tratamiento farmacológico , Cristalografía por Rayos X , Sulfato de Dextran , Perros , Descubrimiento de Drogas , Femenino , Proteínas Ligadas a GPI/antagonistas & inhibidores , Ensayos Analíticos de Alto Rendimiento , Cetonas/química , Ratones , Ratones Endogámicos BALB C , Modelos Moleculares , Piridinas/farmacocinética , Ratas , Relación Estructura-ActividadRESUMEN
Translation of modulation of drug target activity to therapeutic effect is a critical aspect for all drug discovery programs. In this work we describe the profiling of a non-receptor tyrosine-protein kinase (TYK2) inhibitor which shows a functionally relevant potency shift between human and preclinical species (e.g. murine, dog, macaque) in both biochemical and cellular assays. Comparison of the structure and sequence homology of TYK2 between human and preclinical species within the ATP binding site highlights a single amino acid (I960 â V) responsible for the potency shift. Through TYK2 kinase domain mutants and a TYK2 980I knock-in mouse model, we demonstrate that this single amino acid change drives a functionally relevant potency difference that exists between human and all evaluated preclinical species, for a series of TYK2 inhibitors which target the ATP binding site.
Asunto(s)
Descubrimiento de Drogas , Inhibidores de Proteínas Quinasas/farmacología , TYK2 Quinasa/antagonistas & inhibidores , TYK2 Quinasa/química , Adenosina Trifosfato/metabolismo , Secuencia de Aminoácidos , Animales , Sitios de Unión/efectos de los fármacos , Perros , Humanos , Janus Quinasa 1 , Macaca , Ratones , Mutación , Dominios Proteicos/genética , Homología de Secuencia de Aminoácido , Especificidad de la Especie , TYK2 Quinasa/genética , TYK2 Quinasa/metabolismoRESUMEN
Increased fructose consumption and its subsequent metabolism have been implicated in metabolic disorders such as nonalcoholic fatty liver disease and steatohepatitis (NAFLD/NASH) and insulin resistance. Ketohexokinase (KHK) converts fructose to fructose-1-phosphate (F1P) in the first step of the metabolic cascade. Herein we report the discovery of a first-in-class KHK inhibitor, PF-06835919 (8), currently in phase 2 clinical trials. The discovery of 8 was built upon our originally reported, fragment-derived lead 1 and the recognition of an alternative, rotated binding mode upon changing the ribose-pocket binding moiety from a pyrrolidinyl to an azetidinyl ring system. This new binding mode enabled efficient exploration of the vector directed at the Arg-108 residue, leading to the identification of highly potent 3-azabicyclo[3.1.0]hexane acetic acid-based KHK inhibitors by combined use of parallel medicinal chemistry and structure-based drug design.
Asunto(s)
Descubrimiento de Drogas/métodos , Inhibidores Enzimáticos/química , Fructoquinasas/antagonistas & inhibidores , Fructoquinasas/metabolismo , Fructosa/efectos adversos , Enfermedades Metabólicas/enzimología , Animales , Cristalografía por Rayos X , Perros , Relación Dosis-Respuesta a Droga , Inhibidores Enzimáticos/farmacología , Inhibidores Enzimáticos/uso terapéutico , Fructosa/administración & dosificación , Hepatocitos/efectos de los fármacos , Hepatocitos/enzimología , Humanos , Resistencia a la Insulina/fisiología , Masculino , Enfermedades Metabólicas/inducido químicamente , Enfermedades Metabólicas/tratamiento farmacológico , Estructura Secundaria de Proteína , Ratas , Ratas WistarRESUMEN
Tyrosine kinase 2 (TYK2) is a member of the JAK kinase family that regulates signal transduction downstream of receptors for the IL-23/IL-12 pathways and type I interferon family, where it pairs with JAK2 or JAK1, respectively. On the basis of human genetic and emerging clinical data, a selective TYK2 inhibitor provides an opportunity to treat autoimmune diseases delivering a potentially differentiated clinical profile compared to currently approved JAK inhibitors. The discovery of an ATP-competitive pyrazolopyrazinyl series of TYK2 inhibitors was accomplished through computational and structurally enabled design starting from a known kinase hinge binding motif. With understanding of PK/PD relationships, a target profile balancing TYK2 potency and selectivity over off-target JAK2 was established. Lead optimization involved modulating potency, selectivity, and ADME properties which led to the identification of the clinical candidate PF-06826647 (22).
Asunto(s)
Enfermedades Autoinmunes/enzimología , Descubrimiento de Drogas/métodos , Inhibidores de Proteínas Quinasas/química , Inhibidores de Proteínas Quinasas/farmacología , TYK2 Quinasa/antagonistas & inhibidores , Animales , Enfermedades Autoinmunes/tratamiento farmacológico , Humanos , Ratones , Ratones Transgénicos , Microsomas Hepáticos/efectos de los fármacos , Microsomas Hepáticos/enzimología , Inhibidores de Proteínas Quinasas/uso terapéutico , Estructura Secundaria de Proteína , TYK2 Quinasa/química , TYK2 Quinasa/metabolismoRESUMEN
The cell wall in Gram-negative bacteria is surrounded by an outer membrane comprised of charged lipopolysaccharide (LPS) molecules that prevent entry of hydrophobic agents into the cell and protect the bacterium from many antibiotics. The hydrophobic anchor of LPS is lipid A, the biosynthesis of which is essential for bacterial growth and viability. UDP-3-O-(R-3-hydroxymyristoyl)-N-acetylglucosamine deacetylase (LpxC) is an essential zinc-dependant enzyme that catalyzes the conversion of UDP-3-O-(R-3-hydroxymyristoyl)-N-acetylglucosamine to UDP-3-O-(R-3-hydroxymyristoyl)glucosamine and acetate in the biosynthesis of lipid A, and for this reason, LpxC is an attractive target for antibacterial drug discovery. Here we disclose a 1.9 A resolution crystal structure of LpxC from Pseudomonas aeruginosa (paLpxC) in a complex with the potent BB-78485 inhibitor. To our knowledge, this is the first crystal structure of LpxC with a small-molecule inhibitor that shows antibacterial activity against a wide range of Gram-negative pathogens. Accordingly, this structure can provide important information for lead optimization and rational design of the effective small-molecule LpxC inhibitors for successful treatment of Gram-negative infections.
Asunto(s)
Amidohidrolasas/química , Antibacterianos/química , Modelos Moleculares , Naftalenos/química , Sulfonamidas/química , Cristalografía por Rayos X , Diseño de Fármacos , Inhibidores Enzimáticos/químicaRESUMEN
Ongoing interest in the discovery of selective JAK3 inhibitors led us to design novel covalent inhibitors that engage the JAK3 residue Cys909 by cyanamide, a structurally and mechanistically differentiated electrophile from other cysteine reacting groups previously incorporated in JAK3 covalent inhibitors. Through crystallography, kinetic, and computational studies, interaction of cyanamide 12 with Cys909 was optimized leading to potent and selective JAK3 inhibitors as exemplified by 32. In relevant cell-based assays and in agreement with previous results from this group, 32 demonstrated that selective inhibition of JAK3 is sufficient to drive JAK1/JAK3-mediated cellular responses. The contribution from extrahepatic processes to the clearance of cyanamide-based covalent inhibitors was also characterized using metabolic and pharmacokinetic data for 12. This work also gave key insights into a productive approach to decrease glutathione/glutathione S-transferase-mediated clearance, a challenge typically encountered during the discovery of covalent kinase inhibitors.
Asunto(s)
Cianamida/química , Cianamida/farmacología , Janus Quinasa 3/antagonistas & inhibidores , Inhibidores de Proteínas Quinasas/química , Inhibidores de Proteínas Quinasas/farmacología , Animales , Cianamida/farmacocinética , Evaluación Preclínica de Medicamentos , Humanos , Concentración 50 Inhibidora , Janus Quinasa 3/química , Masculino , Modelos Moleculares , Conformación Proteica , Inhibidores de Proteínas Quinasas/farmacocinética , Ratas , Distribución TisularRESUMEN
Cytokine signaling is an important characteristic of autoimmune diseases. Many pro-inflammatory cytokines signal through the Janus kinase (JAK)/Signal transducer and activator of transcription (STAT) pathway. JAK1 is important for the γ-common chain cytokines, interleukin (IL)-6, and type-I interferon (IFN) family, while TYK2 in addition to type-I IFN signaling also plays a role in IL-23 and IL-12 signaling. Intervention with monoclonal antibodies (mAbs) or JAK1 inhibitors has demonstrated efficacy in Phase III psoriasis, psoriatic arthritis, inflammatory bowel disease, and rheumatoid arthritis studies, leading to multiple drug approvals. We hypothesized that a dual JAK1/TYK2 inhibitor will provide additional efficacy, while managing risk by optimizing selectivity against JAK2 driven hematopoietic changes. Our program began with a conformationally constrained piperazinyl-pyrimidine Type 1 ATP site inhibitor, subsequent work led to the discovery of PF-06700841 (compound 23), which is in Phase II clinical development (NCT02969018, NCT02958865, NCT03395184, and NCT02974868).
Asunto(s)
Antituberculosos/farmacología , Artritis Experimental/prevención & control , Janus Quinasa 1/antagonistas & inhibidores , Mycobacterium tuberculosis/efectos de los fármacos , Inhibidores de Proteínas Quinasas/farmacología , Pirazoles/farmacología , Pirimidinas/farmacología , TYK2 Quinasa/antagonistas & inhibidores , Tuberculosis/complicaciones , Animales , Artritis Experimental/inducido químicamente , Artritis Experimental/microbiología , Femenino , Estructura Molecular , Ratas , Ratas Endogámicas Lew , Tuberculosis/microbiologíaRESUMEN
Monoacylglycerol lipase (MAGL) is the main enzyme responsible for degradation of the endocannabinoid 2-arachidonoylglycerol (2-AG) in the CNS. MAGL catalyzes the conversion of 2-AG to arachidonic acid (AA), a precursor to the proinflammatory eicosannoids such as prostaglandins. Herein we describe highly efficient MAGL inhibitors, identified through a parallel medicinal chemistry approach that highlighted the improved efficiency of azetidine and piperidine-derived carbamates. The discovery and optimization of 3-substituted azetidine carbamate irreversible inhibitors of MAGL were aided by the generation of inhibitor-bound MAGL crystal structures. Compound 6, a highly efficient and selective MAGL inhibitor against recombinant enzyme and in a cellular context, was tested in vivo and shown to elevate central 2-AG levels at a 10 mg/kg dose.
Asunto(s)
Azetidinas/farmacología , Carbamatos/farmacología , Inhibidores Enzimáticos/farmacología , Monoacilglicerol Lipasas/antagonistas & inhibidores , Piperidinas/farmacología , Animales , Azetidinas/química , Azetidinas/farmacocinética , Carbamatos/química , Carbamatos/farmacocinética , Línea Celular , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacocinética , Humanos , Ratones Endogámicos C57BL , Modelos Moleculares , Monoacilglicerol Lipasas/metabolismo , Piperidinas/química , Piperidinas/farmacocinética , Proteínas Recombinantes/metabolismoRESUMEN
Increased fructose consumption and its subsequent metabolism have been implicated in hepatic steatosis, dyslipidemia, obesity, and insulin resistance in humans. Since ketohexokinase (KHK) is the principal enzyme responsible for fructose metabolism, identification of a selective KHK inhibitor may help to further elucidate the effect of KHK inhibition on these metabolic disorders. Until now, studies on KHK inhibition with small molecules have been limited due to the lack of viable in vivo pharmacological tools. Herein we report the discovery of 12, a selective KHK inhibitor with potency and properties suitable for evaluating KHK inhibition in rat models. Key structural features interacting with KHK were discovered through fragment-based screening and subsequent optimization using structure-based drug design, and parallel medicinal chemistry led to the identification of pyridine 12.
Asunto(s)
Diseño de Fármacos , Fructoquinasas/antagonistas & inhibidores , Inhibidores de Proteínas Quinasas/química , Inhibidores de Proteínas Quinasas/farmacología , Bibliotecas de Moléculas Pequeñas/química , Bibliotecas de Moléculas Pequeñas/farmacología , Animales , Cristalografía por Rayos X , Fructoquinasas/química , Fructoquinasas/metabolismo , Humanos , Masculino , Simulación del Acoplamiento Molecular , Piridinas/química , Piridinas/farmacología , Ratas , Ratas Sprague-DawleyRESUMEN
Multidrug-resistant Gram-negative pathogens are an emerging threat to human health, and addressing this challenge will require development of new antibacterial agents. This can be achieved through an improved molecular understanding of drug-target interactions combined with enhanced delivery of these agents to the site of action. Herein we describe the first application of siderophore receptor-mediated drug uptake of lactivicin analogues as a strategy that enables the development of novel antibacterial agents against clinically relevant Gram-negative bacteria. We report the first crystal structures of several sideromimic conjugated compounds bound to penicillin binding proteins PBP3 and PBP1a from Pseudomonas aeruginosa and characterize the reactivity of lactivicin and ß-lactam core structures. Results from drug sensitivity studies with ß-lactamase enzymes are presented, as well as a structure-based hypothesis to reduce susceptibility to this enzyme class. Finally, mechanistic studies demonstrating that sideromimic modification alters the drug uptake process are discussed.
Asunto(s)
Bacterias Gramnegativas/metabolismo , Péptidos/metabolismo , Receptores de Superficie Celular/metabolismo , Sideróforos/metabolismo , Bacterias Gramnegativas/efectos de los fármacos , Bacterias Gramnegativas/enzimología , Pruebas de Sensibilidad Microbiana , Péptidos/efectos de los fármacos , Péptidos Cíclicos , beta-Lactamasas/metabolismoRESUMEN
In this paper, we present the synthesis and SAR as well as selectivity, pharmacokinetic, and infection model data for representative analogues of a novel series of potent antibacterial LpxC inhibitors represented by hydroxamic acid.
Asunto(s)
Amidohidrolasas/antagonistas & inhibidores , Antibacterianos/síntesis química , Compuestos de Bifenilo/síntesis química , Ácidos Hidroxámicos/síntesis química , Éteres Fenílicos/síntesis química , Infecciones por Pseudomonas/tratamiento farmacológico , Sulfuros/síntesis química , Sulfonas/síntesis química , Animales , Antibacterianos/química , Antibacterianos/farmacología , Compuestos de Bifenilo/química , Compuestos de Bifenilo/farmacología , Dominio Catalítico , Cristalografía por Rayos X , Farmacorresistencia Bacteriana , Enlace de Hidrógeno , Ácidos Hidroxámicos/química , Ácidos Hidroxámicos/farmacología , Ratones , Modelos Moleculares , Conformación Molecular , Éteres Fenílicos/química , Éteres Fenílicos/farmacología , Pseudomonas aeruginosa , Ratas , Estereoisomerismo , Relación Estructura-Actividad , Sulfuros/química , Sulfuros/farmacología , Sulfonas/química , Sulfonas/farmacologíaRESUMEN
The synthesis and biological activity of a new series of LpxC inhibitors represented by pyridone methylsulfone hydroxamate 2a is presented. Members of this series have improved solubility and free fraction when compared to compounds in the previously described biphenyl methylsulfone hydroxamate series, and they maintain superior Gram-negative antibacterial activity to comparator agents.