Dexpramipexole

Dexpramipexole, also known as R-(+)-Pramipexole, is a neuroprotective agent and weak non-ergoline dopamine agonist. Dexpramipexole has been found to have neuroprotective effects and is being investigated for treatment of amyotrophic lateral sclerosis (ALS). Dexpramipexole reduces mitochondrial reactive oxygen species (ROS) production, inhibits the activation of apoptotic pathways, and increase cell survival in response to a variety of neurotoxins and β-amyloid neurotoxicity. Compared to the S-(-) isomer, Dexpramipexole has much lower dopamine agonist activity.

Dexpramipexole improves bioenergetics and outcome in experimental stroke.[Pubmed:28320070]

Br J Pharmacol. 2018 Jan;175(2):272-283.

BACKGROUND AND PURPOSE: Dexpramipexole, a drug recently tested in patients with amyotrophic lateral sclerosis (ALS,) is able to bind F1Fo ATP synthase and increase mitochondrial ATP production. Here, we have investigated its effects on experimental ischaemic brain injury. EXPERIMENTAL APPROACH: The effects of Dexpramipexole on bioenergetics, Ca(2+) fluxes, electrophysiological functions and death were evaluated in primary neural cultures and hippocampal slices exposed to oxygen-glucose deprivation (OGD). Effects on infarct volumes and neurological functions were also evaluated in mice following proximal or distal middle cerebral artery occlusion (MCAo). Distribution of Dexpramipexole within the ischaemic brain was evaluated by means of mass spectrometry imaging. KEY RESULTS: Dexpramipexole increased mitochondrial ATP production in cultured neurons or glia and reduces energy failure, prevents intracellular Ca(2+) overload and affords cytoprotection when cultures are exposed to OGD. This compound also counteracted ATP depletion, mitochondrial swelling, anoxic depolarization, loss of synaptic activity and neuronal death in hippocampal slices subjected to OGD. Post-ischaemic treatment with Dexpramipexole, at doses consistent with those already used in ALS patients, reduced brain infarct size and ameliorated neuroscore in mice subjected to transient or permanent MCAo. Notably, the concentrations of Dexpramipexole reached within the ischaemic penumbra equalled those found neuroprotective in vitro. CONCLUSION AND IMPLICATIONS: Dexpramipexole, a compound able to increase mitochondrial F1Fo ATP-synthase activity reduced ischaemic brain injury. These findings, together with the excellent brain penetration and favourable safety profile in humans, make Dexpramipexole a drug with realistic translational potential for the treatment of stroke. LINKED ARTICLES: This article is part of a themed section on Inventing New Therapies Without Reinventing the Wheel: The Power of Drug Repurposing. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v175.2/issuetoc.

The targeted eosinophil-lowering effects of dexpramipexole in clinical studies.[Pubmed:28178599]

Blood Cells Mol Dis. 2017 Mar;63:62-65.

Dexpramipexole, an orally bioavailable small molecule previously under clinical development in amyotrophic lateral sclerosis, was observed during routine safety hematology monitoring to demonstrate pronounced, dose- and time-dependent eosinophil-lowering effects, with minor reductions on other leukocyte counts. Analysis of hematology lab values across two double-blind, randomized placebo-controlled clinical trials at total daily doses ranging from 50mg to 300mg demonstrated that Dexpramipexole consistently and markedly lowered peripheral blood eosinophils. This effect developed after 1month on treatment, required 3-4months to reach its maximum, remained constant throughout treatment, and partially recovered to baseline levels upon drug withdrawal. All doses tested were well tolerated. The overall adverse event rate was similar for Dexpramipexole and placebo, and notably with no increase in infection-related adverse events associated with eosinophil-lowering effects. Given the reliance on and insufficiency of off-label chronic corticosteroid therapy for hypereosinophilic syndromes and other eosinophilic-associated diseases (EADs), a need exists for less toxic, more effective, targeted therapeutic alternatives. Further clinical studies are underway to assess the eosinophil-lowering effect of Dexpramipexole in the peripheral blood and target tissues of EAD patients and whether such reductions, if observed, produce clinically important benefits.

The mitochondrial complex V-associated large-conductance inner membrane current is regulated by cyclosporine and dexpramipexole.[Pubmed:25332381]

Mol Pharmacol. 2015 Jan;87(1):1-8.

Inefficiency of oxidative phosphorylation can result from futile leak conductance through the inner mitochondrial membrane. Stress or injury may exacerbate this leak conductance, putting cells, and particularly neurons, at risk of dysfunction and even death when energy demand exceeds cellular energy production. Using a novel method, we have recently described an ion conductance consistent with mitochondrial permeability transition pore (mPTP) within the c-subunit of the ATP synthase. Excitotoxicity, reactive oxygen species-producing stimuli, or elevated mitochondrial matrix calcium opens the channel, which is inhibited by cyclosporine A and ATP/ADP. Here we show that ATP and the neuroprotective drug Dexpramipexole (DEX) inhibited an ion conductance consistent with this c-subunit channel (mPTP) in brain-derived submitochondrial vesicles (SMVs) enriched for F1FO ATP synthase (complex V). Treatment of SMVs with urea denatured extramembrane components of complex V, eliminated DEX- but not ATP-mediated current inhibition, and reduced binding of [(14)C]DEX. Direct effects of DEX on the synthesis and hydrolysis of ATP by complex V suggest that interaction of the compound with its target results in functional conformational changes in the enzyme complex. [(14)C]DEX bound specifically to purified recombinant b and oligomycin sensitivity-conferring protein subunits of the mitochondrial F1FO ATP synthase. Previous data indicate that DEX increased the efficiency of energy production in cells, including neurons. Taken together, these studies suggest that modulation of a complex V-associated inner mitochondrial membrane current is metabolically important and may represent an avenue for the development of new therapeutics for neurodegenerative disorders.

Dexpramipexole is ineffective in two models of ALS related neurodegeneration.[Pubmed:25526593]

PLoS One. 2014 Dec 19;9(12):e91608.

Treatment options for people living with amyotrophic lateral sclerosis (ALS) are limited and ineffective. Recently, Dexpramipexole (RPPX) was advanced into human ALS clinical trials. In the current studies, we investigated RPPX in two parallel screening systems: 1) appropriately powered, sibling-matched, gender-balanced survival efficacy screening in high-copy B6-SJL-SOD1G93A/Gur1 mice, and 2) high-content neuronal survival screening in primary rat cortical neurons transfected with wild-type human TDP43 or mutant human TDP43. In both cases, we exposed the test systems to RPPX levels approximating those achieved in human Phase II clinical investigations. In SOD1G93A mice, no effect was observed on neuromotor disease progression or survival. In primary cortical neurons transfected with either mutant or wild-type human TDP43, a marginally significant improvement in a single indicator of neuronal survival was observed, and only at the 10 microM RPPX treatment. These systems reflect both mutant SOD1- and TDP43-mediated forms of neurodegeneration. The systems also reflect both complex non-cell autonomous and neuronal cell autonomous disease mechanisms. The results of these experiments, taken in context with results produced by other molecules tested in both screening systems, do not argue positively for further study of RPPX in ALS.

Dexpramipexole(KNS-760704), also known as R-(+)-Pramipexole, is a neuroprotective agent and weak non-ergoline dopamine agonist. IC50 Value:

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