RESUMO
Quorum sensing is a process of cell-cell communication that bacteria use to regulate collective behaviors. Quorum sensing depends on the production, detection, and group-wide response to extracellular signal molecules called autoinducers. In many bacterial species, quorum sensing controls virulence factor production. Thus, disrupting quorum sensing is considered a promising strategy to combat bacterial pathogenicity. Several members of a family of naturally produced plant metabolites called flavonoids inhibit Pseudomonas aeruginosa biofilm formation by an unknown mechanism. Here, we explore this family of molecules further, and we demonstrate that flavonoids specifically inhibit quorum sensing via antagonism of the autoinducer-binding receptors, LasR and RhlR. Structure-activity relationship analyses demonstrate that the presence of two hydroxyl moieties in the flavone A-ring backbone are essential for potent inhibition of LasR/RhlR. Biochemical analyses reveal that the flavonoids function non-competitively to prevent LasR/RhlR DNA binding. Administration of the flavonoids to P. aeruginosa alters transcription of quorum sensing-controlled target promoters and suppresses virulence factor production, confirming their potential as anti-infectives that do not function by traditional bacteriocidal or bacteriostatic mechanisms.
Assuntos
Proteínas de Bactérias/antagonistas & inibidores , Flavonoides/farmacologia , Pseudomonas aeruginosa/efeitos dos fármacos , Percepção de Quorum/fisiologia , Transativadores/antagonistas & inibidores , Virulência/efeitos dos fármacos , Regulação Alostérica , Biofilmes/efeitos dos fármacos , Biofilmes/crescimento & desenvolvimento , Pseudomonas aeruginosa/crescimento & desenvolvimento , Percepção de Quorum/efeitos dos fármacos , Bibliotecas de Moléculas Pequenas/farmacologia , Relação Estrutura-AtividadeRESUMO
The long chain free fatty acid receptor 4 (FFA4/GPR120) has recently been recognized as lipid sensor playing important roles in nutrient sensing and inflammation and thus holds potential as a therapeutic target for type 2 diabetes and metabolic syndrome. To explore the effects of stimulating this receptor in animal models of metabolic disease, we initiated work to identify agonists with appropriate pharmacokinetic properties to support progression into in vivo studies. Extensive SAR studies of a series of phenylpropanoic acids led to the identification of compound 29, a FFA4 agonist which lowers plasma glucose in two preclinical models of type 2 diabetes.
Assuntos
Fenilpropionatos/farmacologia , Receptores Acoplados a Proteínas G/agonistas , Animais , Glicemia/efeitos dos fármacos , Diabetes Mellitus Tipo 2/tratamento farmacológico , Modelos Animais de Doenças , Humanos , Masculino , Camundongos , Fenilpropionatos/química , Fenilpropionatos/farmacocinética , Fenilpropionatos/uso terapêutico , Ligação Proteica/efeitos dos fármacos , Ratos , Receptores Acoplados a Proteínas G/metabolismo , Relação Estrutura-AtividadeRESUMO
Traumatic brain injury (TBI) is a significant source of major morbidity and mortality in blunt trauma patients. Computed tomography (CT) is the primary imaging modality of choice for patients with potential brain injury in the acute setting, with magnetic resonance imaging (MRI) playing a role in evaluating equivocal CT findings and may help with determining long-term prognosis and recovery. MRI is being utilized more commonly in the acute and subacute setting of TBI; therefore, radiologists should be familiar with the MRI appearance of the various manifestations of TBI. Here, we review the imaging of common intracranial injuries with illustrative cases comparing CT and MRI.
Assuntos
Lesões Encefálicas/diagnóstico , Imageamento por Ressonância Magnética/métodos , Lesões Encefálicas/epidemiologia , Meios de Contraste , Diagnóstico Diferencial , HumanosRESUMO
A series of 4,4-disubstituted cyclohexylamine based CCR5 antagonists has been designed and synthesized. Their antiviral structure-activity relationship has been extensively explored.
Assuntos
Fármacos Anti-HIV/síntese química , Antagonistas dos Receptores CCR5 , Cicloexilaminas/síntese química , Fármacos Anti-HIV/química , Fármacos Anti-HIV/farmacologia , Linhagem Celular Tumoral , Cicloexilaminas/química , Cicloexilaminas/farmacologia , Infecções por HIV/tratamento farmacológico , Humanos , Receptores CCR5/metabolismo , Relação Estrutura-AtividadeRESUMO
Several series of CCR5 antagonists have been discovered by derivatization at the N-terminal of the piperidine ring of the core template 2. Some derivatives exhibited potent inhibition against HIV-1infection. The pharmacokinetic properties of the lead compounds 11a, 14a, 15b, and 16b have been evaluated in vivo.
Assuntos
Fármacos Anti-HIV/síntese química , Antagonistas dos Receptores CCR5 , Infecções por HIV/tratamento farmacológico , Piperidinas/síntese química , Animais , Fármacos Anti-HIV/farmacologia , Células CHO , Química Farmacêutica/métodos , Cricetinae , Cricetulus , Desenho de Fármacos , HIV-1/metabolismo , Concentração Inibidora 50 , Conformação Molecular , Piperidinas/farmacologia , Estrutura Terciária de Proteína , Ratos , Receptores CCR5/químicaRESUMO
Herein we report the discovery of pyrazolocarboxamides as novel, potent, and kinase selective inhibitors of receptor interacting protein 2 kinase (RIP2). Fragment based screening and design principles led to the identification of the inhibitor series, and X-ray crystallography was used to inform key structural changes. Through key substitutions about the N1 and C5 N positions on the pyrazole ring significant kinase selectivity and potency were achieved. Bridged bicyclic pyrazolocarboxamide 11 represents a selective and potent inhibitor of RIP2 and will allow for a more detailed investigation of RIP2 inhibition as a therapeutic target for autoinflammatory disorders.
RESUMO
OBJECTIVE: Aggressive spinal haemangiomas (those with significant osseous expansion/extraosseous extension) represent approximately 1% of spinal haemangiomas and are usually symptomatic. In this study, we correlate imaging findings with presenting symptomatology, review treatment strategies and their outcomes and propose a treatment algorithm. METHODS: 16 patients with aggressive haemangiomas were retrospectively identified from 1995 to 2013. Imaging was assessed for size, location, CT/MR characteristics, osseous expansion and extraosseous extension. Presenting symptoms, management and outcomes were reviewed. RESULTS: Median patient age was 52 years. Median size was 4.5 cm. Lumbar spine was the commonest location (n = 8), followed by thoracic spine (n = 7) and sacrum (n = 2); one case involved the lumbosacral junction. 12 haemangiomas had osseous expansion; 13 had extraosseous extension [epidural (n = 11), pre-vertebral/paravertebral (n = 10) and foraminal (n = 6)]. On CT, 11 had accentuated trabeculae and 5 showed lysis. On MRI, eight were T1 hyperintense, six were T1 hypointense and all were T2 hyperintense. 11 symptomatic patients underwent treatment: chemical ablation (n = 6), angioembolization (n = 3, 2 had subsequent surgery), radiotherapy (n = 2, 1 primary and 1 adjuvant) and surgery (n = 4). Median follow-up was 20 months. Four of six patients managed only by percutaneous methods had symptom resolution. Three of four patients requiring surgery had symptom resolution. CONCLUSION: Aggressive haemangiomas cause significant morbidity. Treatment is multidisciplinary, with surgery reserved for large lesions and those with focal neurological signs. Minimally invasive procedures may be successful in smaller lesions. ADVANCES IN KNOWLEDGE: Aggressive haemangiomas are rare, but knowledge of their imaging features and treatment strategies enhances the radiologist's role in their management.
Assuntos
Hemangioma/patologia , Neoplasias da Coluna Vertebral/patologia , Adulto , Idoso , Algoritmos , Feminino , Hemangioma/terapia , Humanos , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Neoplasias da Coluna Vertebral/terapia , Tomografia Computadorizada por Raios X , Resultado do TratamentoRESUMO
The apical sodium-dependent bile acid transporter (ASBT) transports bile salts from the lumen of the gastrointestinal (GI) tract to the liver via the portal vein. Multiple pharmaceutical companies have exploited the physiological link between ASBT and hepatic cholesterol metabolism, which led to the clinical investigation of ASBT inhibitors as lipid-lowering agents. While modest lipid effects were demonstrated, the potential utility of ASBT inhibitors for treatment of type 2 diabetes has been relatively unexplored. We initiated a lead optimization effort that focused on the identification of a potent, nonabsorbable ASBT inhibitor starting from the first-generation inhibitor 264W94 (1). Extensive SAR studies culminated in the discovery of GSK2330672 (56) as a highly potent, nonabsorbable ASBT inhibitor which lowers glucose in an animal model of type 2 diabetes and shows excellent developability properties for evaluating the potential therapeutic utility of a nonabsorbable ASBT inhibitor for treatment of patients with type 2 diabetes.
Assuntos
Diabetes Mellitus Tipo 2/tratamento farmacológico , Descoberta de Drogas , Hipoglicemiantes/química , Hipoglicemiantes/farmacologia , Metilaminas/química , Metilaminas/farmacologia , Transportadores de Ânions Orgânicos Dependentes de Sódio/antagonistas & inibidores , Simportadores/antagonistas & inibidores , Tiazepinas/química , Tiazepinas/farmacologia , Animais , Ácidos e Sais Biliares/metabolismo , Cães , Estabilidade de Medicamentos , Células HEK293 , Humanos , Hipoglicemiantes/metabolismo , Hipoglicemiantes/uso terapêutico , Masculino , Metilaminas/metabolismo , Metilaminas/uso terapêutico , Camundongos , Ratos , Solubilidade , Tiazepinas/metabolismo , Tiazepinas/uso terapêuticoRESUMO
We recently described ( J. Med. Chem. 2008 , 51 , 6538 - 6546 ) a novel class of CCR5 antagonists with strong anti-HIV potency. Herein, we detail SAR converting leads 1 and 2 to druglike molecules. The pivotal structural motif enabling this transition was the secondary sulfonamide substituent. Further fine-tuning of the substituent pattern in the sulfonamide paved the way to enhancing potency and bioavailability and minimizing hERG inhibition, resulting in discovery of clinical compound 122 (GSK163929).
Assuntos
Fármacos Anti-HIV/química , Fármacos Anti-HIV/farmacologia , Compostos Azabicíclicos/química , Compostos Azabicíclicos/farmacologia , Antagonistas dos Receptores CCR5 , Canais de Potássio Éter-A-Go-Go/antagonistas & inibidores , HIV-1/efeitos dos fármacos , Piperidinas/química , Piperidinas/farmacologia , Animais , Fármacos Anti-HIV/síntese química , Fármacos Anti-HIV/metabolismo , Área Sob a Curva , Compostos Azabicíclicos/síntese química , Compostos Azabicíclicos/metabolismo , Benzimidazóis , Cães , Desenho de Fármacos , Canais de Potássio Éter-A-Go-Go/genética , Canais de Potássio Éter-A-Go-Go/metabolismo , Haplorrinos , Humanos , Piperidinas/síntese química , Piperidinas/metabolismo , Ratos , Relação Estrutura-Atividade , Sulfonamidas , TropanosRESUMO
We describe robust chemical approaches toward putative CCR5 scaffolds designed in our laboratories. Evaluation of analogues in the (125)I-[MIP-1beta] binding and Ba-L-HOS antiviral assays resulted in the discovery of 64 and 68 in the 4,4-disubstitited piperidine class H, both potent CCR5 ligands (pIC 50 = 8.30 and 9.00, respectively) and HIV-1 inhibitors (pIC 50 = 7.80 and 7.84, respectively, in Ba-L-HOS assay). In addition, 64 and 68 were bioavailable in rodents, establishing them as lead molecules for further optimization toward CCR5 clinical candidates.
Assuntos
Antivirais/síntese química , Antivirais/farmacologia , HIV-1/efeitos dos fármacos , Piperidinas/síntese química , Piperidinas/farmacologia , Receptores CCR5/química , Receptores CCR5/metabolismo , Antivirais/química , Avaliação Pré-Clínica de Medicamentos , Ligantes , Estrutura Molecular , Piperidinas/química , Relação Estrutura-AtividadeRESUMO
A series of bis-aryl substituted guanidines have been discovered as potent NPY Y5 antagonists. The SAR and in vitro metabolic stability of these compounds are discussed.
Assuntos
Guanidinas/síntese química , Guanidinas/farmacologia , Receptores de Neuropeptídeo Y/antagonistas & inibidores , Animais , Células CHO , Cricetinae , Cricetulus , Guanidinas/química , Estrutura Molecular , Ensaio Radioligante , Relação Estrutura-AtividadeRESUMO
Mice lacking syndecan-1 are viable, fertile and have morphologically normal skin, hair and ocular surface epithelia. While studying the response of these mice to corneal epithelial and skin wounding, we identified defects in epithelial cell proliferation and regulation of integrin expression. mRNA profiling of corneal epithelial tissues obtained from wild-type and syndecan-1(-/-) mice suggest that these defects result from differences in overall gene transcription. In the cornea, syndecan-1(-/-) epithelial cells migrate more slowly, show reduced localization of alpha9 integrin during closure of wounds and fail to increase their proliferation rate 24 hours after wounding. In the skin, we did not document a migration defect after full thickness wounds but did observe cell proliferation delays and reduced localization of alpha9 integrin in the syndecan-1(-/-) epidermis after dermabrasion. Despite increased cell proliferation rates in the uninjured syndecan-1(-/-) epidermis and the corneal epithelium, morphologically normal epithelial thickness is maintained prior to injury; however, wounding is accompanied by prolonged hypoplasia in both tissues. Analyses of integrin protein levels in extracts from full thickness skin, revealed increased levels of alpha3 and alpha9 integrins both prior to injury and after hair removal in syndecan-1(-/-) mice but no increase 2 days after dermabrasion. These data for the first time show involvement of alpha9 integrin in skin wound healing and demonstrate essential roles for syndecan-1 in mediating cell proliferation and regulation of integrin expression in normal and wounded epithelial tissues.