RESUMO
Genome-wide association studies have identified risk loci linked to inflammatory bowel disease (IBD)1-a complex chronic inflammatory disorder of the gastrointestinal tract. The increasing prevalence of IBD in industrialized countries and the augmented disease risk observed in migrants who move into areas of higher disease prevalence suggest that environmental factors are also important determinants of IBD susceptibility and severity2. However, the identification of environmental factors relevant to IBD and the mechanisms by which they influence disease has been hampered by the lack of platforms for their systematic investigation. Here we describe an integrated systems approach, combining publicly available databases, zebrafish chemical screens, machine learning and mouse preclinical models to identify environmental factors that control intestinal inflammation. This approach established that the herbicide propyzamide increases inflammation in the small and large intestine. Moreover, we show that an AHR-NF-κB-C/EBPß signalling axis operates in T cells and dendritic cells to promote intestinal inflammation, and is targeted by propyzamide. In conclusion, we developed a pipeline for the identification of environmental factors and mechanisms of pathogenesis in IBD and, potentially, other inflammatory diseases.
Assuntos
Meio Ambiente , Herbicidas , Inflamação , Doenças Inflamatórias Intestinais , Intestinos , Animais , Camundongos , Inflamação/induzido quimicamente , Inflamação/etiologia , Inflamação/imunologia , Inflamação/patologia , Doenças Inflamatórias Intestinais/induzido quimicamente , Doenças Inflamatórias Intestinais/etiologia , Doenças Inflamatórias Intestinais/imunologia , Doenças Inflamatórias Intestinais/patologia , Peixe-Zebra , Aprendizado de Máquina , Bases de Dados Factuais , Modelos Animais de Doenças , Intestinos/efeitos dos fármacos , Intestinos/imunologia , Intestinos/metabolismo , Intestinos/patologia , NF-kappa B , Proteína beta Intensificadora de Ligação a CCAAT , Receptores de Hidrocarboneto Arílico , Linfócitos T/efeitos dos fármacos , Linfócitos T/imunologia , Linfócitos T/metabolismo , Células Dendríticas/efeitos dos fármacos , Células Dendríticas/imunologia , Células Dendríticas/metabolismo , Herbicidas/efeitos adversosRESUMO
OBJECTIVE: Parkinson disease (PD) has useful symptomatic treatments that do not slow the neurodegenerative process, and no significant disease-modifying treatments are approved. A key therapeutic target in PD is α-synuclein (αS), which is both genetically implicated and accumulates in Lewy bodies rich in vesicles and other lipid membranes. Reestablishing αS homeostasis is a central goal in PD. Based on previous lipidomic analyses, we conducted a mouse trial of a stearoyl-coenzyme A desaturase (SCD) inhibitor ("5b") that prevented αS-positive vesicular inclusions and cytotoxicity in cultured human neurons. METHODS: Oral dosing and brain activity of 5b were established in nontransgenic mice. 5b in drinking water was given to mice expressing wild-type human αS (WT) or an amplified familial PD αS mutation (E35K + E46K + E61K ["3K"]) beginning near the onset of nigral and cortical neurodegeneration and the robust PD-like motor syndrome in 3K. Motor phenotypes, brain cytopathology, and SCD-related lipid changes were quantified in 5b- versus placebo-treated mice. Outcomes were compared to effects of crossing 3K to SCD1-/- mice. RESULTS: 5b treatment reduced αS hyperphosphorylation in E46K-expressing human neurons, in 3K neural cultures, and in both WT and 3K αS mice. 5b prevented subtle gait deficits in WT αS mice and the PD-like resting tremor and progressive motor decline of 3K αS mice. 5b also increased αS tetramers and reduced proteinase K-resistant lipid-rich aggregates. Similar benefits accrued from genetically deleting 1 SCD allele, providing target validation. INTERPRETATION: Prolonged reduction of brain SCD activity prevented PD-like neuropathology in multiple PD models. Thus, an orally available SCD inhibitor potently ameliorates PD phenotypes, positioning this approach to treat human α-synucleinopathies. ANN NEUROL 2021;89:74-90.
Assuntos
Doença de Parkinson/prevenção & controle , alfa-Sinucleína/genética , Animais , Encéfalo/patologia , Humanos , Corpos de Lewy/patologia , Camundongos Transgênicos , Neurônios/metabolismo , Doença de Parkinson/genética , Fenótipo , alfa-Sinucleína/metabolismoRESUMO
Spinal muscular atrophy (SMA) is a neurodegenerative disorder that results from mutations in the SMN1 gene, leading to survival motor neuron (SMN) protein deficiency. One therapeutic strategy for SMA is to identify compounds that enhance the expression of the SMN2 gene, which normally only is a minor contributor to functional SMN protein production, but which is unaffected in SMA. A recent high-throughput screening campaign identified a 3,4-dihydro-4-phenyl-2(1H)-quinolinone derivative (2) that increases the expression of SMN2 by 2-fold with an EC50â¯=â¯8.3⯵M. A structure-activity relationship (SAR) study revealed that the array of tolerated substituents, on either the benzo portion of the quinolinone or the 4-phenyl, was very narrow. However, the lactam ring of the quinolinone was more amenable to modifications. For example, the quinazolinone (9a) and the benzoxazepin-2(3H)-one (19) demonstrated improved potency and efficacy for increase in SMN2 expression as compared to 2.
Assuntos
Quinolonas/química , Proteína 2 de Sobrevivência do Neurônio Motor/metabolismo , Animais , Linhagem Celular , Ciclização , Expressão Gênica/efeitos dos fármacos , Humanos , Camundongos , Microssomos Hepáticos/metabolismo , Atrofia Muscular Espinal/metabolismo , Atrofia Muscular Espinal/patologia , Quinolonas/farmacologia , RNA Mensageiro/metabolismo , Solubilidade , Relação Estrutura-Atividade , Proteína 2 de Sobrevivência do Neurônio Motor/genéticaRESUMO
Synucleinopathy (Parkinson's disease (PD); Lewy body dementia) disease-modifying treatments represent a huge unmet medical need. Although the PD-causing protein α-synuclein (αS) interacts with lipids and fatty acids (FA) physiologically and pathologically, targeting FA homeostasis for therapeutics is in its infancy. We identified the PD-relevant target stearoyl-coA desaturase: inhibiting monounsaturated FA synthesis reversed PD phenotypes. However, lipid degradation also generates FA pools. Here, we identify the rate-limiting lipase enzyme, LIPE, as a candidate target. Decreasing LIPE in human neural cells reduced αS inclusions. Patient αS triplication vs. corrected neurons had increased pSer129 and insoluble αS and decreased αS tetramer:monomer ratios. LIPE inhibition rescued all these and the abnormal unfolded protein response. LIPE inhibitors decreased pSer129 and restored tetramer:monomer equilibrium in αS E46K-expressing human neurons. LIPE reduction in vivo alleviated αS-induced dopaminergic neurodegeneration in Caenorhabditis elegans. Co-regulating FA synthesis and degradation proved additive in rescuing PD phenotypes, signifying co-targeting as a therapeutic strategy.
RESUMO
Spinal muscular atrophy (SMA) is a motor neuron disease and the leading genetic cause of infant mortality. SMA results from insufficient survival motor neuron (SMN) protein due to alternative splicing. Antisense oligonucleotides, gene therapy and splicing modifiers recently received FDA approval. Although severe SMA transgenic mouse models have been beneficial for testing therapeutic efficacy, models mimicking milder cases that manifest post-infancy have proven challenging to develop. We established a titratable model of mild and moderate SMA using the splicing compound NVS-SM2. Administration for 30 d prevented development of the SMA phenotype in severe SMA mice, which typically show rapid weakness and succumb by postnatal day 11. Furthermore, administration at day eight resulted in phenotypic recovery. Remarkably, acute dosing limited to the first 3 d of life significantly enhanced survival in two severe SMA mice models, easing the burden on neonates and demonstrating the compound as suitable for evaluation of follow-on therapies without potential drug-drug interactions. This pharmacologically tunable SMA model represents a useful tool to investigate cellular and molecular pathogenesis at different stages of disease.
Assuntos
Atrofia Muscular Espinal/tratamento farmacológico , Atrofia Muscular Espinal/genética , Piperidinas/administração & dosagem , Pirazóis/administração & dosagem , Piridazinas/administração & dosagem , Splicing de RNA/efeitos dos fármacos , Animais , Animais Recém-Nascidos , Sobrevivência Celular/efeitos dos fármacos , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Estimativa de Kaplan-Meier , Camundongos , Camundongos Transgênicos , Neurônios Motores/metabolismo , Atrofia Muscular Espinal/metabolismo , Fenótipo , Proteína 2 de Sobrevivência do Neurônio Motor/genética , Proteína 2 de Sobrevivência do Neurônio Motor/metabolismo , Tempo para o TratamentoRESUMO
Targeted delivery of drugs to tumor cells, which circumvent resistance mechanisms and induce cell killing, is a lingering challenge that requires innovative solutions. Here, we provide two bioengineered strategies in which nanotechnology is blended with cancer medicine to preferentially target distinct mechanisms of drug resistance. In the first 'case study', we demonstrate the use of lipid-drug conjugates that target molecular signaling pathways, which result from taxane-induced drug tolerance via cell surface lipid raft accumulations. Through a small molecule drug screen, we identify a kinase inhibitor that optimally destroys drug tolerant cancer cells and conjugate it to a rationally-chosen lipid scaffold, which enhances anticancer efficacy in vitro and in vivo. In the second 'case study', we address resistance mechanisms that can occur through exocytosis of nanomedicines. Using adenocarcinoma HeLa and MCF-7 cells, we describe the use of gold nanorod and nanoporous vehicles integrated with an optical antenna for on-demand, photoactivation at ~650 nm enabling release of payloads into cells including cytotoxic anthracyclines. Together, these provide two approaches, which exploit engineering strategies capable of circumventing distinct resistance barriers and induce killing by multimodal, including nanophotonic mechanisms.
RESUMO
Cell-cell interactions control the physiology and pathology of the central nervous system (CNS). To study astrocyte cell interactions in vivo, we developed rabies barcode interaction detection followed by sequencing (RABID-seq), which combines barcoded viral tracing and single-cell RNA sequencing (scRNA-seq). Using RABID-seq, we identified axon guidance molecules as candidate mediators of microglia-astrocyte interactions that promote CNS pathology in experimental autoimmune encephalomyelitis (EAE) and, potentially, multiple sclerosis (MS). In vivo cell-specific genetic perturbation EAE studies, in vitro systems, and the analysis of MS scRNA-seq datasets and CNS tissue established that Sema4D and Ephrin-B3 expressed in microglia control astrocyte responses via PlexinB2 and EphB3, respectively. Furthermore, a CNS-penetrant EphB3 inhibitor suppressed astrocyte and microglia proinflammatory responses and ameliorated EAE. In summary, RABID-seq identified microglia-astrocyte interactions and candidate therapeutic targets.
Assuntos
Astrócitos/fisiologia , Comunicação Celular , Sistema Nervoso Central/patologia , Encefalomielite Autoimune Experimental/fisiopatologia , Microglia/fisiologia , Esclerose Múltipla/fisiopatologia , Análise de Célula Única , Animais , Antígenos CD/metabolismo , Encéfalo/patologia , Encéfalo/fisiopatologia , Sistema Nervoso Central/fisiopatologia , Encefalomielite Autoimune Experimental/patologia , Efrina-B3/metabolismo , Herpesvirus Suídeo 1/genética , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Mitocôndrias/metabolismo , Esclerose Múltipla/patologia , NF-kappa B/metabolismo , Proteínas do Tecido Nervoso/metabolismo , RNA-Seq , Espécies Reativas de Oxigênio/metabolismo , Receptor EphB3/antagonistas & inibidores , Receptor EphB3/metabolismo , Receptores de Superfície Celular/metabolismo , Semaforinas/metabolismo , Transdução de Sinais , Linfócitos T/fisiologia , Serina-Treonina Quinases TOR/metabolismoRESUMO
The transient receptor potential cation channel, subfamily V, member 1 (TRPV1) is a non-selective cation channel that can be activated by a wide range of noxious stimuli, including capsaicin, acid, and heat. Blockade of TRPV1 activation by selective antagonists is under investigation in an attempt to identify novel agents for pain treatment. During pre-clinical development, the 1,8-naphthyridine 2 demonstrated unacceptably high levels of irreversible covalent binding. Replacement of the 1,8-naphthyridine core by a pyrido[2,3-b]pyrazine led to the discovery of compound 26 which was shown to have significantly lower potential for the formation of reactive metabolites. Compound 26 was characterized as an orally bioavailable TRPV1 antagonist with moderate brain penetration. In vivo, 26 significantly attenuated carrageenan-induced thermal hyperalgesia (CITH) and dose-dependently reduced complete Freund's adjuvant (CFA)-induced chronic inflammatory pain after oral administration.
Assuntos
Pirazinas/química , Canais de Cátion TRPV/antagonistas & inibidores , Administração Oral , Animais , Cães , Avaliação Pré-Clínica de Medicamentos , Humanos , Hiperalgesia/induzido quimicamente , Hiperalgesia/tratamento farmacológico , Macaca mulatta , Microssomos Hepáticos/metabolismo , Naftiridinas/síntese química , Naftiridinas/química , Dor/tratamento farmacológico , Pirazinas/farmacocinética , Pirazinas/uso terapêutico , Ratos , Canais de Cátion TRPV/metabolismoRESUMO
Gulf War illness is associated with a combination of exposure to war-related chemical agents and traumatic stress. Currently, there are no effective treatments, and the pathophysiology remains elusive. Neurological problems are among the most commonly reported symptoms. In this study, we investigated the glutamatergic system in the hippocampi of mice exposed to war-related chemical agents and stress. Mice developed Gulf War illness-like symptoms, including mood deficits, cognitive impairments, and fatigue. They exhibited the following pathological changes in hippocampi: elevated extracellular glutamate levels, impaired glutamatergic synapses, astrocyte atrophy, loss of interneurons, and decreased neurogenesis. LDN/OSU-215111 is a small-molecule that can strengthen the structure and function of both the astrocytic processes and the glutamatergic synapses that together form the tripartite synapses. We found that LDN/OSU-215111 effectively prevented the development of mood and cognitive deficits in mice when treatment was implemented immediately following the exposure. Moreover, when symptoms were already present, LDN/OSU-215111 still significantly ameliorated these deficits; impressively, benefits were sustained one month after treatment cessation, indicating disease modification. LDN/OSU-215111 effectively normalized hippocampal pathological changes. Overall, this study provides strong evidence that restoration of tripartite glutamatergic synapses by LDN/OSU-215111 is a potential therapy for Gulf War illness.
RESUMO
BACKGROUND: The lack of effective treatment options for Alzheimer's disease (AD) is of momentous societal concern. Synaptic loss is the hallmark of AD that correlates best with impaired memory and occurs early in the disease process, before the onset of clinical symptoms. We have developed a small-molecule, pyridazine-based series that enhances the structure and function of both the glial processes and the synaptic boutons that form the tripartite synapse. Previously, we have shown that these pyridazine derivatives exhibit profound efficacy in an amyloid precursor protein AD model. Here, we evaluated the efficacy of an advanced compound, LDN/OSU-0215111, in rTg4510 mice-an aggressive tauopathy model. METHODS: rTg4510 mice were treated orally with vehicle or LDN/OSU-0215111 (10 mg/kg) daily from the early symptomatic stage (2 months old) to moderate (4 months old) and severe (8 months old) disease stages. At each time point, mice were subjected to a battery of behavioral tests to assess the activity levels and cognition. Also, tissue collections were performed on a subset of mice to analyze the tripartite synaptic changes, neurodegeneration, gliosis, and tau phosphorylation as assessed by immunohistochemistry and Western blotting. At 8 months of age, a subset of rTg4510 mice treated with compound was switched to vehicle treatment and analyzed behaviorally and biochemically 30 days after treatment cessation. RESULTS: At both the moderate and severe disease stages, compound treatment normalized cognition and behavior as well as reduced synaptic loss, neurodegeneration, tau hyperphosporylation, and neuroinflammation. Importantly, after 30 days of treatment cessation, the benefits of compound treatment were sustained, indicating disease modification. We also found that compound treatment rapidly and robustly reduced tau hyperphosphorylation/deposition possibly via the inhibition of GSK3ß. CONCLUSIONS: The results show that LDN/OSU-0215111 provides benefits for multiple aspects of tauopathy-dependent pathology found in Alzheimer's disease including tripartite synapse normalization and reduction of toxic tau burden, which, in turn, likely accounted for normalized cognition and activity levels in compound-treated rTg4510 mice. This study, in combination with our previous work regarding the benefit of pyridazine derivatives against amyloid-dependent pathology, strongly supports pyridazine derivatives as a viable, clinically relevant, and disease-modifying treatment for many of the facets of Alzheimer's disease.
Assuntos
Doença de Alzheimer/tratamento farmacológico , Transportador 2 de Aminoácido Excitatório , Piridazinas/farmacologia , Sinapses/efeitos dos fármacos , Doença de Alzheimer/metabolismo , Doença de Alzheimer/patologia , Animais , Comportamento Animal/efeitos dos fármacos , Modelos Animais de Doenças , Camundongos , Camundongos Transgênicos , Piridazinas/administração & dosagem , Piridazinas/análise , Sinapses/patologiaRESUMO
The design, synthesis and structure-activity relationship studies of a novel series of CRF-1 receptor antagonists, the 2-arylpyrimidines, are described. The effects of substitution on the aromatic ring and the pyrimidine core on CRF-1 receptor binding were investigated. A number of compounds with K(i) values below 10 nM and lipophilicity in a minimally acceptable range for a CNS drug (cLogP<5) were discovered.
Assuntos
Química Farmacêutica/métodos , Pirimidinas/química , Pirimidinas/síntese química , Receptores de Hormônio Liberador da Corticotropina/antagonistas & inibidores , Animais , Sítios de Ligação , Química Farmacêutica/instrumentação , Desenho de Fármacos , Humanos , Cinética , Modelos Químicos , Conformação Molecular , Estrutura Molecular , Ratos , Ratos Sprague-Dawley , Solubilidade , Relação Estrutura-AtividadeRESUMO
The design, synthesis and structure-activity relationships of a novel series of CRF-1 receptor antagonist, the 1-aryl-4-alkylaminoisoquinolines, is described. The effects of substitution on the aromatic ring, the amino group and the isoquinoline core on CRF-1 receptor binding were investigated.
Assuntos
Desenho de Fármacos , Isoquinolinas/síntese química , Isoquinolinas/farmacologia , Receptores de Hormônio Liberador da Corticotropina/antagonistas & inibidores , Ansiedade/tratamento farmacológico , Sítios de Ligação , Técnicas de Química Combinatória , Depressão/tratamento farmacológico , Humanos , Isoquinolinas/química , Estrutura Molecular , Relação Estrutura-Atividade , Células Tumorais CultivadasRESUMO
The design, synthesis, and structure-activity studies of a novel series of BK B(1) receptor antagonists based on a 1-benzylbenzimidazole chemotype are described. A number of compounds, for example, 38g, with excellent affinity for the cynomolgus macaque and rat bradykinin B(1) receptor were discovered.
Assuntos
Benzimidazóis/síntese química , Benzimidazóis/farmacologia , Antagonistas de Receptor B1 da Bradicinina , Animais , Benzimidazóis/química , Técnicas de Química Combinatória , Cães , Desenho de Fármacos , Estrutura Molecular , Ratos , Relação Estrutura-AtividadeRESUMO
A focused SAR exploration of the lead 4-aminoquinazoline TRPV1 antagonist 2 led to the discovery of compound 18. In rats, compound 18 is readily absorbed following oral dosing and demonstrates excellent in vivo potency and efficacy in an acute inflammatory pain model.
Assuntos
Aminoquinolinas/farmacologia , Química Farmacêutica/métodos , Canais de Cátion TRPV/antagonistas & inibidores , Aminoquinolinas/química , Animais , Cães , Desenho de Fármacos , Canal de Potássio ERG1 , Canais de Potássio Éter-A-Go-Go/química , Inflamação/tratamento farmacológico , Cinética , Modelos Químicos , Conformação Molecular , Dor/tratamento farmacológico , Preparações Farmacêuticas/química , Ratos , Canais de Cátion TRPV/químicaRESUMO
Excitatory amino acid transporter 2 (EAAT2) is primarily located in perisynaptic astrocytic processes (PAP) where it plays a critical role in synaptic glutamate homeostasis. Dysregulation of EAAT2 at the translational level has been implicated in a myriad of neurological diseases. We previously discovered that pyridazine analogs can activate EAAT2 translation. Here, we sought to further refine the site and mechanism of compound action. We found that in vivo, compound treatment increased EAAT2 expression only in the PAP of astrocytes where EAAT2 mRNA also was identified. Direct application of compound to isolated PAP induced de novo EAAT2 protein synthesis, indicating that compound activates translation locally in the PAP. Using a screening process, we identified a set of PAP proteins that are rapidly up-regulated following compound treatment and a subset of these PAP proteins may be locally synthesized in the PAP. Importantly, these identified proteins are associated with the structural and functional capacity of the PAP, indicating compound enhanced plasticity of the PAP. Concomitantly, we found that pyridazine analogs increase synaptic protein expression in the synapse and enhance hippocampal long-term potentiation. This was not dependent upon compound-mediated local translation in neurons. This suggests that compound enhances the structural and functional capacity of the PAP which in turn facilitates enhanced plasticity of the tripartite synapse. Overall, this provides insight into the mechanism action site of pyridazine derivatives as well as the growing appreciation of the dynamic regulation and functional aspects of the PAP at the tripartite synapse.
Assuntos
Astrócitos/efeitos dos fármacos , Fármacos do Sistema Nervoso Central/farmacologia , Plasticidade Neuronal/efeitos dos fármacos , Biossíntese de Proteínas/efeitos dos fármacos , Piridazinas/farmacologia , Sinapses/efeitos dos fármacos , Animais , Astrócitos/citologia , Astrócitos/metabolismo , Transportador 2 de Aminoácido Excitatório/metabolismo , Microdomínios da Membrana/efeitos dos fármacos , Microdomínios da Membrana/metabolismo , Camundongos , Plasticidade Neuronal/fisiologia , Neurônios/citologia , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Prosencéfalo/citologia , Prosencéfalo/efeitos dos fármacos , Prosencéfalo/metabolismo , Proteoma/efeitos dos fármacos , RNA Mensageiro/metabolismo , Sinapses/metabolismo , Sinaptossomos/efeitos dos fármacos , Sinaptossomos/metabolismo , Técnicas de Cultura de TecidosRESUMO
Spinal muscular atrophy (SMA) is the leading genetic cause of infant death. We previously developed a high-throughput assay that employs an SMN2-luciferase reporter allowing identification of compounds that act transcriptionally, enhance exon recognition, or stabilize the SMN protein. We describe optimization and characterization of an analog suitable for in vivo testing. Initially, we identified analog 4m that had good in vitro properties but low plasma and brain exposure in a mouse PK experiment due to short plasma stability; this was overcome by reversing the amide bond and changing the heterocycle. Thiazole 27 showed excellent in vitro properties and a promising mouse PK profile, making it suitable for in vivo testing. This series post-translationally stabilizes the SMN protein, unrelated to global proteasome or autophagy inhibition, revealing a novel therapeutic mechanism that should complement other modalities for treatment of SMA.
Assuntos
Anilidas/farmacologia , Benzamidas/farmacologia , Isoxazóis/farmacologia , Sondas Moleculares , Atrofia Muscular Espinal/terapia , Processamento de Proteína Pós-Traducional , Quinolonas/farmacologia , Proteína 1 de Sobrevivência do Neurônio Motor/metabolismo , Tiazóis/farmacologia , Anilidas/farmacocinética , Anilidas/uso terapêutico , Área Sob a Curva , Benzamidas/farmacocinética , Benzamidas/uso terapêutico , Linhagem Celular , Descoberta de Drogas , Meia-Vida , Humanos , Isoxazóis/farmacocinética , Isoxazóis/uso terapêutico , Estabilidade Proteica , Quinolonas/farmacocinética , Quinolonas/uso terapêutico , Relação Estrutura-Atividade , Tiazóis/farmacocinética , Tiazóis/uso terapêuticoRESUMO
Spinal muscular atrophy (SMA) is an autosomal recessive neurodegenerative disease resulting from pathologically low levels of survival motor neuron (SMN) protein. The majority of mRNA from the SMN2 allele undergoes alternative splicing and excludes critical codons, causing an SMN protein deficiency. While there is currently no FDA-approved treatment for SMA, early therapeutic efforts have focused on testing repurposed drugs such as phenylbutyrate (2), valproic acid (3), riluzole (6), hydroxyurea (7), and albuterol (9), none of which has demonstrated clinical effectiveness. More recently, clinical trials have focused on novel small-molecule compounds identified from high-throughput screening and medicinal chemistry optimization such as olesoxime (11), CK-2127107, RG7800, LMI070, and RG3039 (17). In this paper, we review both repurposed drugs and small-molecule compounds discovered following medicinal chemistry optimization for the potential treatment of SMA.
Assuntos
Atrofia Muscular Espinal/tratamento farmacológico , Fármacos Neuroprotetores/uso terapêutico , Bibliotecas de Moléculas Pequenas/uso terapêutico , Química Farmacêutica , Humanos , Estrutura Molecular , Fármacos Neuroprotetores/síntese química , Fármacos Neuroprotetores/química , Bibliotecas de Moléculas Pequenas/síntese química , Bibliotecas de Moléculas Pequenas/químicaRESUMO
Glutamatergic systems play a critical role in cognitive functions and are known to be defective in Alzheimer's disease (AD) patients. Previous literature has indicated that glial glutamate transporter EAAT2 plays an essential role in cognitive functions and that loss of EAAT2 protein is a common phenomenon observed in AD patients and animal models. In the current study, we investigated whether restored EAAT2 protein and function could benefit cognitive functions and pathology in APPSw,Ind mice, an animal model of AD. A transgenic mouse approach via crossing EAAT2 transgenic mice with APPSw,Ind. mice and a pharmacological approach using a novel EAAT2 translational activator, LDN/OSU-0212320, were conducted. Findings from both approaches demonstrated that restored EAAT2 protein function significantly improved cognitive functions, restored synaptic integrity, and reduced amyloid plaques. Importantly, the observed benefits were sustained one month after compound treatment cessation, suggesting that EAAT2 is a potential disease modifier with therapeutic potential for AD.
Assuntos
Doença de Alzheimer/metabolismo , Transportador 2 de Aminoácido Excitatório/metabolismo , Piridazinas/farmacologia , Piridinas/farmacologia , Doença de Alzheimer/patologia , Doença de Alzheimer/terapia , Peptídeos beta-Amiloides/metabolismo , Animais , Células Cultivadas , Cognição/efeitos dos fármacos , Cognição/fisiologia , Modelos Animais de Doenças , Transportador 2 de Aminoácido Excitatório/genética , Camundongos Transgênicos , Neurônios/metabolismo , Neurônios/patologia , Placa Amiloide/genética , Placa Amiloide/metabolismoRESUMO
[reaction: see text] Novel and highly efficient syntheses of oxazolo[4,5-c]quinoline-4(5H)-ones (1) and thiazolo[4,5-c]quinoline-4(5H)-ones (2) from ethyl 2-chlorooxazole-4-carboxylate (4) and ethyl 2-bromo-5-chlorothiazole-4-carboxylate (13), respectively, are described.
RESUMO
The regiocontrolled synthesis of 2,5-disubstituted and 2,4,5-trisubstituted thiazoles from ethyl 2-bromo-5-chloro-4-thiazolecarboxylate 1 using sequential palladium-catalyzed coupling reactions is described. [reaction: see text]