RESUMO
The sodium glucose co-transporter 2 (SGLT2) has received considerable attention in recent years as a target for the treatment of type 2 diabetes mellitus. This report describes the design, synthesis and structure-activity relationship (SAR) of C-glycosides with benzyltriazolopyridinone and phenylhydantoin as the aglycone moieties as novel SGLT2 inhibitors. Compounds 5p and 33b demonstrated high potency in inhibiting SGLT2 and high selectivity against SGLT1. The in vitro ADMET properties of these compounds will also be discussed.
Assuntos
Desenho de Fármacos , Glicosídeos/farmacologia , Fenitoína/análogos & derivados , Piridonas/farmacologia , Inibidores do Transportador 2 de Sódio-Glicose , Triazóis/farmacologia , Relação Dose-Resposta a Droga , Glicosídeos/síntese química , Glicosídeos/química , Humanos , Estrutura Molecular , Fenitoína/química , Fenitoína/farmacologia , Piridonas/síntese química , Piridonas/química , Transportador 2 de Glucose-Sódio , Relação Estrutura-Atividade , Triazóis/síntese química , Triazóis/químicaRESUMO
The design, synthesis, and structure-activity relationships (SAR) of a series of N-((1-(4-(propylsulfonyl)piperazin-1-yl)cycloalkyl)methyl)benzamide inhibitors of glycine transporter-1 (GlyT-1) are described. Optimization of the benzamide and central ring components of the core scaffold led to the identification of a GlyT-1 inhibitor that demonstrated in vivo activity in a rodent cerebral spinal fluid (CSF) glycine model.
Assuntos
Benzamidas/química , Benzamidas/farmacologia , Proteínas da Membrana Plasmática de Transporte de Glicina/antagonistas & inibidores , Animais , Benzamidas/síntese química , Glicina/líquido cefalorraquidiano , Proteínas da Membrana Plasmática de Transporte de Glicina/metabolismo , Células HEK293 , Humanos , Microssomos Hepáticos/metabolismo , Piperazinas/síntese química , Piperazinas/química , Piperazinas/farmacologia , Ratos , Relação Estrutura-AtividadeRESUMO
Three new compounds named leporizines A-C have been isolated from an Aspergillus sp. strain. Their structures were elucidated by analysis of 1D and 2D NMR spectra. Leporizines A and B were isolated during dereplication of hits from a high-throughput screening campaign for correctors of the cystic fibrosis transmembrane conductance regulator (CFTR), and leporizine C was isolated while preparing additional material for characterization of leporizines A and B. CFTR activity observed for leporizines A and B was highly correlated with cell toxicity and was determined to be a nonspecific effect. Leporizine C was not cytotoxic to cells and did not elicit a response in the CFTR assays. To the best of our knowledge, leporizines A-C represent the first examples of this unusual epithiodiketopiperazine skeleton.
Assuntos
Antineoplásicos/isolamento & purificação , Aspergillus/química , Dicetopiperazinas/isolamento & purificação , Antineoplásicos/química , Antineoplásicos/farmacologia , Regulador de Condutância Transmembrana em Fibrose Cística/efeitos dos fármacos , Dicetopiperazinas/química , Dicetopiperazinas/farmacologia , Ensaios de Seleção de Medicamentos Antitumorais , Células Hep G2 , Humanos , Estrutura Molecular , Montana , Mutação , Ressonância Magnética Nuclear Biomolecular , Mucosa RespiratóriaRESUMO
A new series of 5-(pyridinon-1-yl)indazoles with MCH-1 antagonist activity were synthesized. Potential cardiovascular risk for these compounds was assessed based upon their interaction with the hERG potassium channel in a mini-patch clamp assay. Selected compounds were studied in a 5-day diet-induced obese mouse model to evaluate their potential use as weight loss agents. Structural modification of the 5-(pyridinon-1-yl)indazoles to give 5-(furopyridinon-5-yl)indazoles provided compounds with enhanced pharmacokinetic properties and improved efficacy.
Assuntos
Indazóis/farmacologia , Obesidade/tratamento farmacológico , Receptores do Hormônio Hipofisário/antagonistas & inibidores , Animais , Fármacos Antiobesidade/química , Fármacos Antiobesidade/farmacologia , Doenças Cardiovasculares/induzido quimicamente , Canais de Potássio Éter-A-Go-Go/efeitos dos fármacos , Humanos , Indazóis/farmacocinética , Indazóis/uso terapêutico , Camundongos , Relação Estrutura-AtividadeRESUMO
A new series of 4-aryl-1-(indazol-5-yl)pyridin-2(1H)ones possessing MCH-1 receptor antagonism is presented. Suzuki coupling of boronic acids with key triflate 6 allowed rapid generation of a range of analogs. The SAR of the MCH-1 receptor was explored with a variety of aryl and heterocyclic moieties. Selected compounds were studied in a five-day diet induced obese mouse model to evaluate their potential use as weight loss agents.
Assuntos
Fármacos Antiobesidade/química , Obesidade/tratamento farmacológico , Piridinas/química , Receptores do Hormônio Hipofisário/antagonistas & inibidores , Animais , Fármacos Antiobesidade/farmacologia , Camundongos , Piridinas/farmacologia , Relação Estrutura-AtividadeRESUMO
A new series of tetrahydrocarbolines with potent MCH-1 antagonist activity were synthesized, using a conformationally constrained design approach towards optimizing pharmacokinetic properties. Two compounds from this series were progressed to a 5-day diet-induced obesity mouse screening model to evaluate their potential as weight loss agents. Both compounds produced a highly significant reduction in weight, which was attributed to their improved pharmacokinetic profile.
Assuntos
Fármacos Antiobesidade/química , Carbolinas/química , Obesidade/tratamento farmacológico , Receptores do Hormônio Hipofisário/antagonistas & inibidores , Animais , Fármacos Antiobesidade/farmacologia , Peso Corporal/efeitos dos fármacos , Carbolinas/farmacologia , Carbolinas/uso terapêutico , Camundongos , Relação Estrutura-AtividadeRESUMO
Three new antibiotics, neopyrrolomycins B (1), C (2), and D (3), with potent activity against Gram-positive pathogens were discovered. They exhibited MIC values < 1 microg/mL versus a number of resistant strains. The compounds were obtained from the ethyl acetate extracts of a Streptomyces sp. after purification by column chromatography and RP-HPLC. Their structures were elucidated using X-ray crystallography (1) and NMR spectroscopy (2 and 3).
Assuntos
Antibacterianos/isolamento & purificação , Antibacterianos/farmacologia , Streptomyces/química , Antibacterianos/química , Cristalografia por Raios X , Farmacorresistência Bacteriana/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Enterococcus faecium/efeitos dos fármacos , Escherichia coli/efeitos dos fármacos , Humanos , Klebsiella pneumoniae/efeitos dos fármacos , Staphylococcus aureus Resistente à Meticilina/efeitos dos fármacos , Testes de Sensibilidade Microbiana , Conformação Molecular , Estrutura Molecular , Ressonância Magnética Nuclear Biomolecular , Pseudomonas aeruginosa/efeitos dos fármacos , Pirróis/química , Pirróis/isolamento & purificação , Pirróis/farmacologia , Streptococcus pneumoniae/efeitos dos fármacos , Vancomicina/farmacologiaRESUMO
Two new xanthone antibiotics, citreamicin delta (1) and epsilon (2), with potent activity against Gram-positive pathogens including multidrug-resistant Staphylococcus aureus (MDRSA) were discovered. Compounds 1 and 2 exhibited MIC values < 1 microg/mL versus a number of resistant strains. The compounds were obtained from EtOAc extracts of Streptomyces vinaceus and were purified by countercurrent chromatography and reversed-phase HPLC. Their structures were elucidated using primarily NMR and mass spectroscopy.
Assuntos
Farmacorresistência Bacteriana Múltipla/efeitos dos fármacos , Bactérias Gram-Positivas/efeitos dos fármacos , Staphylococcus aureus/efeitos dos fármacos , Antibacterianos/química , Antibacterianos/farmacologia , Cromatografia Líquida de Alta Pressão , Humanos , Testes de Sensibilidade Microbiana , Estrutura Molecular , Oxazóis/química , Oxazóis/farmacologiaRESUMO
Resistance to currently available antibiotics has become a widely recognized crisis in the medical community. To address this, many companies and researchers are refocusing their attention towards natural products, which have an excellent track record of producing effective antibacterial drugs. The AMRI natural product library was screened for activity against multi-drug resistant Staphylococcus aureus (MDRSA). The active samples were counter screened for cytotoxicity against the human hepatocellular carcinoma HepG2 cell line to determine an in vitro therapeutic index (in vitro TI). Those samples with a high in vitro TI were selected for fractionation and dereplication. This led to the discovery of a new anthracycline structure. This metabolite, named mutactimycin E (1), exhibited moderate activity against several gram positive organisms. Here we report the isolation, structure elucidation and biological activities of this new compound.
Assuntos
Antraciclinas/farmacologia , Antibacterianos/farmacologia , Bactérias Gram-Positivas/efeitos dos fármacos , Antraciclinas/química , Antraciclinas/isolamento & purificação , Antraciclinas/toxicidade , Antibacterianos/química , Antibacterianos/isolamento & purificação , Antibacterianos/toxicidade , Linhagem Celular , Hepatócitos/efeitos dos fármacos , Humanos , Estrutura Molecular , Bibliotecas de Moléculas Pequenas , Análise EspectralRESUMO
We previously disclosed the discovery of rationally designed N-((1-(4-(propylsulfonyl)piperazin-1-yl)cycloalkyl)methyl)benzamide inhibitors of glycine transporter-1 (GlyT-1), represented by analogues 10 and 11. We describe herein further structure-activity relationship exploration of this series via an optimization strategy that primarily focused on the sulfonamide and benzamide appendages of the scaffold. These efforts led to the identification of advanced leads possessing a desirable balance of excellent in vitro GlyT-1 potency and selectivity, favorable ADME and in vitro pharmacological profiles, and suitable pharmacokinetic and safety characteristics. Representative analogue (+)-67 exhibited robust in vivo activity in the cerebral spinal fluid glycine biomarker model in both rodents and nonhuman primates. Furthermore, rodent microdialysis experiments also demonstrated that oral administration of (+)-67 significantly elevated extracellular glycine levels within the medial prefrontal cortex (mPFC).
Assuntos
Benzamidas/química , Benzamidas/farmacologia , Proteínas da Membrana Plasmática de Transporte de Glicina/antagonistas & inibidores , Animais , Benzamidas/síntese química , Benzamidas/farmacocinética , Glicina/líquido cefalorraquidiano , Glicina/metabolismo , Proteínas da Membrana Plasmática de Transporte de Glicina/metabolismo , Macaca fascicularis , Masculino , Metilação , Piperazinas/síntese química , Piperazinas/química , Piperazinas/farmacocinética , Piperazinas/farmacologia , Ratos , Ratos Sprague-Dawley , Relação Estrutura-AtividadeRESUMO
Mathematical models of metabolism from bacterial systems biology have proven their utility across multiple fields, for example metabolic engineering, growth phenotype simulation, and biological discovery. The usefulness of the models stems from their ability to compute a link between genotype and phenotype, but their ability to accurately simulate gene-gene interactions has not been investigated extensively. Here we assess how accurately a metabolic model for Escherichia coli computes one particular type of gene-gene interaction, synthetic lethality, and find that the accuracy rate is between 25% and 43%. The most common failure modes were incorrect computation of single gene essentiality and biological information that was missing from the model. Moreover, we performed virtual and biological screening against several synthetic lethal pairs to explore whether two-compound formulations could be found that inhibit the growth of Gram-negative bacteria. One set of molecules was identified that, depending on the concentrations, inhibits E. coli and S. enterica serovar Typhimurium in an additive or antagonistic manner. These findings pinpoint specific ways in which to improve the predictive ability of metabolic models, and highlight one potential application of systems biology to drug discovery and translational medicine.
Assuntos
Antibacterianos/farmacologia , Escherichia coli O157/genética , Genes Letais/genética , Klebsiella pneumoniae/genética , Salmonella typhimurium/genética , Biologia de Sistemas/métodos , Yersinia pestis/genética , Antibacterianos/síntese química , Combinação de Medicamentos , Descoberta de Drogas , Escherichia coli O157/crescimento & desenvolvimento , Escherichia coli O157/metabolismo , Doenças Transmitidas por Alimentos/microbiologia , Klebsiella pneumoniae/crescimento & desenvolvimento , Klebsiella pneumoniae/metabolismo , Testes de Sensibilidade Microbiana , Modelos Biológicos , Modelos Teóricos , Salmonella typhimurium/crescimento & desenvolvimento , Salmonella typhimurium/metabolismo , Yersinia pestis/crescimento & desenvolvimento , Yersinia pestis/metabolismoRESUMO
Mathematical models of biochemical networks form a cornerstone of bacterial systems biology. Inconsistencies between simulation output and experimental data point to gaps in knowledge about the fundamental biology of the organism. One such inconsistency centers on the gene aldA in Escherichia coli: it is essential in a computational model of E. coli metabolism, but experimentally it is not. Here, we reconcile this disparity by providing evidence that aldA and prpC form a synthetic lethal pair, as the double knockout could only be created through complementation with a plasmid-borne copy of aldA. Moreover, virtual and biological screening against the two proteins led to a set of compounds that inhibited the growth of E. coli and Salmonella enterica serovar Typhimurium synergistically at 100-200 µM individual concentrations. These results highlight the power of metabolic models to drive basic biological discovery and their potential use to discover new combination antibiotics.
RESUMO
Through medicinal chemistry lead optimization studies focused on calculated properties and guided by X-ray crystallography and computational modeling, potent pan-JNK inhibitors were identified that showed submicromolar activity in a cellular assay. Using in vitro ADME profiling data, 9t was identified as possessing favorable permeability and a low potential for efflux, but it was rapidly cleared in liver microsomal incubations. In a mouse pharmacokinetics study, compound 9t was brain-penetrant after oral dosing, but exposure was limited by high plasma clearance. Brain exposure at a level expected to support modulation of a pharmacodynamic marker in mouse was achieved when the compound was coadministered with the pan-cytochrome P450 inhibitor 1-aminobenzotriazole.