ABSTRACT
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.
Subject(s)
Central Nervous System/cytology , Central Nervous System/metabolism , Cytoprotection/genetics , Fumarates/pharmacology , NF-E2-Related Factor 2/physiology , Neurons/metabolism , Oxidative Stress/genetics , Signal Transduction/genetics , Animals , Cells, Cultured , Central Nervous System/drug effects , Cytoprotection/drug effects , Humans , Mice , Mice, Inbred C57BL , Mice, Knockout , NF-E2-Related Factor 2/deficiency , Neurons/drug effects , Neuroprotective Agents/pharmacology , Oxidative Stress/drug effects , Signal Transduction/drug effectsABSTRACT
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.
Subject(s)
Amyloid Precursor Protein Secretases/antagonists & inhibitors , Anti-Inflammatory Agents, Non-Steroidal/chemistry , Enzyme Inhibitors/chemistry , Phenylacetates/chemistry , Piperidines/chemistry , Administration, Oral , Amyloid Precursor Protein Secretases/metabolism , Amyloid beta-Peptides/metabolism , Animals , Anti-Inflammatory Agents, Non-Steroidal/chemical synthesis , Anti-Inflammatory Agents, Non-Steroidal/pharmacokinetics , Brain/metabolism , Drug Design , Drug Evaluation, Preclinical , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/pharmacokinetics , Mice , Peptide Fragments/metabolism , Phenylacetates/chemical synthesis , Phenylacetates/pharmacokinetics , Piperidines/chemical synthesis , Piperidines/pharmacokinetics , RatsABSTRACT
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.
