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2.
Nature ; 537(7618): 50-6, 2016 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-27582220

RESUMO

Alzheimer's disease (AD) is characterized by deposition of amyloid-ß (Aß) plaques and neurofibrillary tangles in the brain, accompanied by synaptic dysfunction and neurodegeneration. Antibody-based immunotherapy against Aß to trigger its clearance or mitigate its neurotoxicity has so far been unsuccessful. Here we report the generation of aducanumab, a human monoclonal antibody that selectively targets aggregated Aß. In a transgenic mouse model of AD, aducanumab is shown to enter the brain, bind parenchymal Aß, and reduce soluble and insoluble Aß in a dose-dependent manner. In patients with prodromal or mild AD, one year of monthly intravenous infusions of aducanumab reduces brain Aß in a dose- and time-dependent manner. This is accompanied by a slowing of clinical decline measured by Clinical Dementia Rating-Sum of Boxes and Mini Mental State Examination scores. The main safety and tolerability findings are amyloid-related imaging abnormalities. These results justify further development of aducanumab for the treatment of AD. Should the slowing of clinical decline be confirmed in ongoing phase 3 clinical trials, it would provide compelling support for the amyloid hypothesis.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/psicologia , Peptídeos beta-Amiloides/antagonistas & inibidores , Peptídeos beta-Amiloides/metabolismo , Anticorpos Monoclonais Humanizados/uso terapêutico , Placa Amiloide/tratamento farmacológico , Placa Amiloide/metabolismo , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/metabolismo , Doença de Alzheimer/patologia , Amiloide/efeitos dos fármacos , Amiloide/metabolismo , Peptídeos beta-Amiloides/química , Animais , Anticorpos Monoclonais Humanizados/administração & dosagem , Anticorpos Monoclonais Humanizados/efeitos adversos , Anticorpos Monoclonais Humanizados/farmacocinética , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Ensaios Clínicos Fase III como Assunto , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Feminino , Humanos , Masculino , Camundongos , Camundongos Transgênicos , Pessoa de Meia-Idade , Modelos Biológicos , Placa Amiloide/patologia , Agregação Patológica de Proteínas/tratamento farmacológico , Solubilidade
3.
Neuropharmacology ; 103: 57-68, 2016 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-26690893

RESUMO

Reducing the production of larger aggregation-prone amyloid ß-peptides (Aß) remains an untested therapeutic approach for reducing the appearance and growth of Aß plaques in the brain, which are a hallmark pathological feature of Alzheimer's disease. γ-Secretase modulators (GSMs) are therapeutics that impact γ-secretase-dependent cleavage of amyloid precursor protein to promote the production of shorter Aß peptides that are less prone to aggregation and plaque deposition. This is accomplished without inhibiting overall γ-secretase function and cleavage of other substrates, which is believed to be a source of deleterious side effects. Here, we report the pharmacokinetic and pharmacodynamic properties of BIIB042, a novel bioavailable and brain-penetrant GSM. In cell-based assays, BIIB042 reduced the levels of Aß42, increased the levels of Aß38 and had little effect on the levels of Aß40, the most abundant Aß species. Similar pharmacodynamic properties were confirmed in the central nervous system and in plasma of mice and rats, and also in plasma of cynomolgus monkeys after a single oral dose of BIIB042. BIIB042 reduced Aß42 levels and Aß plaque burden in Tg2576 mice, which overexpress human amyloid precursor protein and serve as a model system for Alzheimer's disease. BIIB042 did not inhibit cleavage of other γ-secretase substrates in cell-based and in vivo signaling and cleavage assays. The pharmacodynamic effects of lowering Aß42 in the central nervous system coupled with demonstrated efficacy in reducing plaque pathology suggests modulation of γ-secretase, with molecules like BIIB042, is a compelling therapeutic approach for the treatment of Alzheimer's disease.


Assuntos
Aldeídos/farmacocinética , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/enzimologia , Secretases da Proteína Precursora do Amiloide/metabolismo , Peptídeos beta-Amiloides/metabolismo , Encéfalo/efeitos dos fármacos , Encéfalo/enzimologia , Aldeídos/administração & dosagem , Peptídeos beta-Amiloides/sangue , Animais , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Macaca fascicularis , Masculino , Camundongos , Placa Amiloide/metabolismo , Isoformas de Proteínas/sangue , Ratos , Ratos Endogâmicos F344
4.
J Pharmacol Exp Ther ; 341(1): 274-84, 2012 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-22267202

RESUMO

Oxidative stress is central to the pathology of several neurodegenerative diseases, including multiple sclerosis, and therapeutics designed to enhance antioxidant potential could have clinical value. The objective of this study was to characterize the potential direct neuroprotective effects of dimethyl fumarate (DMF) and its primary metabolite monomethyl fumarate (MMF) on cellular resistance to oxidative damage in primary cultures of central nervous system (CNS) cells and further explore the dependence and function of the nuclear factor (erythroid-derived 2)-like 2 (Nrf2) pathway in this process. Treatment of animals or primary cultures of CNS cells with DMF or MMF resulted in increased nuclear levels of active Nrf2, with subsequent up-regulation of canonical antioxidant target genes. DMF-dependent up-regulation of antioxidant genes in vivo was lost in mice lacking Nrf2 [Nrf2(-/-)]. DMF or MMF treatment increased cellular redox potential, glutathione, ATP levels, and mitochondrial membrane potential in a concentration-dependent manner. Treating astrocytes or neurons with DMF or MMF also significantly improved cell viability after toxic oxidative challenge in a concentration-dependent manner. This effect on viability was lost in cells that had eliminated or reduced Nrf2. These data suggest that DMF and MMF are cytoprotective for neurons and astrocytes against oxidative stress-induced cellular injury and loss, potentially via up-regulation of an Nrf2-dependent antioxidant response. These data also suggest DMF and MMF may function through improving mitochondrial function. The clinical utility of DMF in multiple sclerosis is being explored through phase III trials with BG-12, which is an oral therapeutic containing DMF as the active ingredient.


Assuntos
Sistema Nervoso Central/citologia , Sistema Nervoso Central/metabolismo , Citoproteção/genética , Fumaratos/farmacologia , Fator 2 Relacionado a NF-E2/fisiologia , Neurônios/metabolismo , Estresse Oxidativo/genética , Transdução de Sinais/genética , Animais , Células Cultivadas , Sistema Nervoso Central/efeitos dos fármacos , Citoproteção/efeitos dos fármacos , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Fator 2 Relacionado a NF-E2/deficiência , Neurônios/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos
5.
Bioorg Med Chem Lett ; 21(24): 7277-80, 2011 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-22061640

RESUMO

Starting from literature examples of nonsteroidal anti-inflammatory drugs (NSAIDs)-type carboxylic acid γ-secretase modulators (GSMs) and using a scaffold design approach, we identified 4-aminomethylphenylacetic acid 4 with a desirable γ-secretase modulation profile. Scaffold optimization led to the discovery of a novel chemical series, represented by 6b, having improved brain penetration. Further SAR studies provided analog 6q that exhibited a good pharmacological profile. Oral administration of 6q significantly reduced brain Aß42 levels in mice and rats.


Assuntos
Secretases da Proteína Precursora do Amiloide/antagonistas & inibidores , Anti-Inflamatórios não Esteroides/química , Inibidores Enzimáticos/química , Fenilacetatos/química , Piperidinas/química , Administração Oral , Secretases da Proteína Precursora do Amiloide/metabolismo , Peptídeos beta-Amiloides/metabolismo , Animais , Anti-Inflamatórios não Esteroides/síntese química , Anti-Inflamatórios não Esteroides/farmacocinética , Encéfalo/metabolismo , Desenho de Fármacos , Avaliação Pré-Clínica de Medicamentos , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacocinética , Camundongos , Fragmentos de Peptídeos/metabolismo , Fenilacetatos/síntese química , Fenilacetatos/farmacocinética , Piperidinas/síntese química , Piperidinas/farmacocinética , Ratos
6.
Brain ; 134(Pt 3): 678-92, 2011 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-21354971

RESUMO

Inflammation and oxidative stress are thought to promote tissue damage in multiple sclerosis. Thus, novel therapeutics enhancing cellular resistance to free radicals could prove useful for multiple sclerosis treatment. BG00012 is an oral formulation of dimethylfumarate. In a phase II multiple sclerosis trial, BG00012 demonstrated beneficial effects on relapse rate and magnetic resonance imaging markers indicative of inflammation as well as axonal destruction. First we have studied effects of dimethylfumarate on the disease course, central nervous system, tissue integrity and the molecular mechanism of action in an animal model of chronic multiple sclerosis: myelin oligodendrocyte glycoprotein induced experimental autoimmune encephalomyelitis in C57BL/6 mice. In the chronic phase of experimental autoimmune encephalomyelitis, preventive or therapeutic application of dimethylfumarate ameliorated the disease course and improved preservation of myelin, axons and neurons. In vitro, the application of fumarates increased murine neuronal survival and protected human or rodent astrocytes against oxidative stress. Application of dimethylfumarate led to stabilization of the transcription factor nuclear factor (erythroid-derived 2)-related factor 2, activation of nuclear factor (erythroid-derived 2)-related factor 2-dependent transcriptional activity and accumulation of NADP(H) quinoline oxidoreductase-1 as a prototypical target gene. Furthermore, the immediate metabolite of dimethylfumarate, monomethylfumarate, leads to direct modification of the inhibitor of nuclear factor (erythroid-derived 2)-related factor 2, Kelch-like ECH-associated protein 1, at cysteine residue 151. In turn, increased levels of nuclear factor (erythroid-derived 2)-related factor 2 and reduced protein nitrosylation were detected in the central nervous sytem of dimethylfumarate-treated mice. Nuclear factor (erythroid-derived 2)-related factor 2 was also upregulated in the spinal cord of autopsy specimens from untreated patients with multiple sclerosis. In dimethylfumarate-treated mice suffering from experimental autoimmune encephalomyelitis, increased immunoreactivity for nuclear factor (erythroid-derived 2)-related factor 2 was detected by confocal microscopy in neurons of the motor cortex and the brainstem as well as in oligodendrocytes and astrocytes. In mice deficient for nuclear factor (erythroid-derived 2)-related factor 2 on the same genetic background, the dimethylfumarate mediated beneficial effects on clinical course, axon preservation and astrocyte activation were almost completely abolished thus proving the functional relevance of this transcription factor for the neuroprotective mechanism of action. We conclude that the ability of dimethylfumarate to activate nuclear factor (erythroid-derived 2)-related factor 2 may offer a novel cytoprotective modality that further augments the natural antioxidant responses in multiple sclerosis tissue and is not yet targeted by other multiple sclerosis therapies.


Assuntos
Encefalomielite Autoimune Experimental/prevenção & controle , Fumaratos/uso terapêutico , Fator 2 Relacionado a NF-E2/metabolismo , Fármacos Neuroprotetores/uso terapêutico , Transdução de Sinais/efeitos dos fármacos , 2',3'-Nucleotídeo Cíclico Fosfodiesterases/metabolismo , Aldeído Redutase/metabolismo , Animais , Antígenos de Diferenciação/metabolismo , Antioxidantes/metabolismo , Astrócitos/efeitos dos fármacos , Astrócitos/imunologia , Axônios/metabolismo , Axônios/patologia , Complexo CD3/metabolismo , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Cromatografia Líquida de Alta Pressão/métodos , Citocinas/metabolismo , Modelos Animais de Doenças , Embrião de Mamíferos , Encefalomielite Autoimune Experimental/etiologia , Feminino , Fumaratos/farmacologia , Regulação da Expressão Gênica/efeitos dos fármacos , Glicoproteínas/efeitos adversos , Proteínas de Fluorescência Verde/genética , Humanos , Peróxido de Hidrogênio/farmacologia , Espectrometria de Massas , Camundongos , Camundongos Endogâmicos C57BL , Neurônios Motores/citologia , Neurônios Motores/efeitos dos fármacos , Neurônios Motores/metabolismo , Esclerose Múltipla/metabolismo , Esclerose Múltipla/patologia , Proteínas da Mielina/metabolismo , Glicoproteína Mielina-Oligodendrócito , NAD(P)H Desidrogenase (Quinona)/metabolismo , Fármacos Neuroprotetores/farmacologia , Proteínas Nogo , Estresse Oxidativo/efeitos dos fármacos , Fragmentos de Peptídeos/efeitos adversos , RNA Interferente Pequeno/farmacologia , Sono/fisiologia , Medula Espinal/citologia , Estatísticas não Paramétricas , Espectrometria de Massas em Tandem/métodos , Fatores de Tempo , Transfecção
7.
ACS Med Chem Lett ; 2(10): 786-91, 2011 Oct 13.
Artigo em Inglês | MEDLINE | ID: mdl-24900267

RESUMO

We have investigated a novel series of acid-derived γ-secretase modulators as a potential treatment of Alzheimer's disease. Optimization based on cellular potency and brain pharmacodynamics after oral dosing led to the discovery of 10a (BIIB042). Compound 10a is a potent γ-secretase modulator, which lowered Aß42, increased Aß38, but had little to no effect on Aß40 levels both in vitro and in vivo. In addition, compound 10a did not affect Notch signaling in our in vitro assessment. Compound 10a demonstrated excellent pharmacokinetic parameters in multiple species. Oral administration of 10a significantly reduced brain Aß42 levels in CF-1 mice and Fischer rats, as well as plasma Aß42 levels in cynomolgus monkeys. Compound 10a was selected as a candidate for preclinical safety evaluation.

8.
Bioorg Med Chem Lett ; 20(7): 2264-9, 2010 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-20188554
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