Dexpramipexole
(Synonyms: 右旋普拉克索; (R)-Pramipexole; R-(+)-Pramipexole; KNS-760704) 目录号 : GC35847Dexpramipexole(KNS-760704)也叫R-(+)-Pramipexole,是神经保护剂,是弱的非麦角类多巴胺受体激动剂。
Cas No.:104632-28-2
Sample solution is provided at 25 µL, 10mM.
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Dexpramipexole(KNS-760704), also known as R-(+)-Pramipexole, is a neuroprotective agent and weak non-ergoline dopamine agonist. IC50 Value:Target: Dopamine ReceptorDexpramipexole 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.
[1]. Rudnicki SA, Berry JD, Ingersoll E, et al. Dexpramipexole effects on functional decline and survival in subjects with amyotrophic lateral sclerosis in a Phase II study: subgroup analysis of demographic and clinical characteristics. Amyotroph Lateral Scler [2]. Alavian KN, Dworetzky SI, Bonanni L, et al. Effects of dexpramipexole on brain mitochondrial conductances and cellular bioenergetic efficiency. Brain Res. 2012 Mar 29;1446:1-11. [3]. Cudkowicz M, Bozik ME, Ingersoll EW, et al. The effects of dexpramipexole (KNS-760704) in individuals with amyotrophic lateral sclerosis. Nat Med. 2011 Nov 20;17(12):1652-6. [4]. Bozik ME, Mather JL, Kramer WG, et al. Safety, tolerability, and pharmacokinetics of KNS-760704 (dexpramipexole) in healthy adult subjects. J Clin Pharmacol. 2011 Aug;51(8):1177-85. [5]. Cheah BC, Kiernan MC. Dexpramipexole, the R(+) enantiomer of pramipexole, for the potential treatment of amyotrophic lateral sclerosis. IDrugs. 2010 Dec;13(12):911-20.
Cas No. | 104632-28-2 | SDF | |
别名 | 右旋普拉克索; (R)-Pramipexole; R-(+)-Pramipexole; KNS-760704 | ||
Canonical SMILES | NC1=NC(CC[C@@H](NCCC)C2)=C2S1 | ||
分子式 | C10H17N3S | 分子量 | 211.33 |
溶解度 | Soluble in DMSO | 储存条件 | Store at -20°C |
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10 mM | 0.4732 mL | 2.366 mL | 4.7319 mL |
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Dexpramipexole attenuates myocardial ischemia/reperfusion injury through upregulation of mitophagy
Eur J Pharmacol 2021 May 15;899:173962.PMID:33610599DOI:10.1016/j.ejphar.2021.173962.
Reperfusion causes undesirable damage to the ischemic myocardium while restoring the blood flow. In this study, we evaluated the effects of Dexpramipexole (DPX) on myocardial injury induced by ischemia/reperfusion (I/R) in-vivo and the hypoxia/reoxygenation (HR) in-vitro and examined the functional mechanisms of DPX. DPX protected cells against H/R-induced mitochondrial dysfunction and prevented H/R damage. Both myocardial infarct size and tissue damage due to I/R was reduced upon DPX treatment. We discovered that DPX enhanced mitophagy in-vivo and in-vitro, which was accompanied by enhanced expression of PINK1 and Parkin. Knock-down of PINK1 and Parkin by specific siRNAs reversed DPX-induced inhibition of myocardial I/R injury. These findings suggest that DPX might protect against myocardial injury via PINK1 and Parkin.
Dexpramipexole improves bioenergetics and outcome in experimental stroke
Br J Pharmacol 2018 Jan;175(2):272-283.PMID:28320070DOI:10.1111/bph.13790.
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, Ca2+ 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 Ca2+ 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.
Dexpramipexole, the R(+) enantiomer of pramipexole, for the potential treatment of amyotrophic lateral sclerosis
IDrugs 2010 Dec;13(12):911-20.PMID:21154151doi
Dexpramipexole (KNS-760704), the R(+) enantiomer of pramipexole, is under development by Knopp Neurosciences and Biogen Idec as a potential neuroprotective therapy for amyotrophic lateral sclerosis (ALS), a universally fatal neurodegenerative disease. Pramipexole, exclusively the S(-) enantiomer, is a non-ergot dopaminergic autoreceptor agonist that is currently marketed for use in the treatment of Parkinson's disease and restless legs syndrome. Pramipexole has been proposed to exert a broad spectrum of neuroprotective properties, primarily through antioxidant effects, inhibiting apoptotic enzymes and preserving mitochondrial structure and activity. More recent work has suggested that pramipexole possesses anti-excitotoxic properties, raising the possibility of beneficial effects in patients with ALS. However, pramipexole has high intrinsic dopaminergic receptor activity and, consequently, dose-limiting side effects, including orthostatic hypotension and hallucination, are frequent. Dexpramipexole exhibits significantly lower affinity for dopaminergic receptors, thereby making it unlikely to be associated with dopaminergic side effects. In clinical trials to date, Dexpramipexole has been safe and well tolerated at doses up to 67-fold higher than the maximum recommended daily dose of pramipexole in patients with Parkinson's disease, and has demonstrated signs of neuroprotective benefit. This report summarizes the chemical and pharmacological properties of Dexpramipexole and describes the potential utility of the drug in the pharmaceutical development pipeline.
Dexpramipexole as an oral steroid-sparing agent in hypereosinophilic syndromes
Blood 2018 Aug 2;132(5):501-509.PMID:29739754DOI:10.1182/blood-2018-02-835330.
Hypereosinophilic syndromes (HESs) are a heterogeneous group of disorders characterized by peripheral eosinophilia and eosinophil-related end organ damage. Whereas most patients respond to glucocorticoid (GC) therapy, high doses are often necessary, and side effects are common. Dexpramipexole (KNS-760704), an orally bioavailable synthetic aminobenzothiazole, showed an excellent safety profile and was coincidentally noted to significantly decrease absolute eosinophil counts (AECs) in a phase 3 trial for amyotrophic lateral sclerosis. This proof-of-concept study was designed to evaluate Dexpramipexole (150 mg orally twice daily) as a GC-sparing agent in HESs. Dual primary end points were (1) the proportion of subjects with ≥50% decrease in the minimum effective GC dose (MED) to maintain AEC <1000/μL and control clinical symptoms, and (2) the MED after 12 weeks of Dexpramipexole (MEDD) as a percentage of the MED at week 0. Out of 10 subjects, 40% (95% confidence interval [CI], 12%, 74%) achieved a ≥50% reduction in MED, and the MEDD/MED ratio was significantly <100% (median, 66%; 95% CI, 6%, 98%; P = .03). All adverse events were self-limited, and none led to drug discontinuation. Affected tissue biopsy samples in 2 subjects showed normalization of pathology and depletion of eosinophils on Dexpramipexole. Bone marrow biopsy samples after 12 weeks of Dexpramipexole showed selective absence of mature eosinophils in responders. Dexpramipexole appears promising as a GC-sparing agent without apparent toxicity in a subset of subjects with GC-responsive HESs. Although the exact mechanism of action is unknown, preliminary data suggest that Dexpramipexole may affect eosinophil maturation in the bone marrow. This study was registered at www.clinicaltrials.gov as #NCT02101138.
From Riluzole to Dexpramipexole via Substituted-Benzothiazole Derivatives for Amyotrophic Lateral Sclerosis Disease Treatment: Case Studies
Molecules 2020 Jul 22;25(15):3320.PMID:32707914DOI:10.3390/molecules25153320.
The 1,3-benzothiazole (BTZ) ring may offer a valid option for scaffold-hopping from indole derivatives. Several BTZs have clinically relevant roles, mainly as CNS medicines and diagnostic agents, with riluzole being one of the most famous examples. Riluzole is currently the only approved drug to treat amyotrophic lateral sclerosis (ALS) but its efficacy is marginal. Several clinical studies have demonstrated only limited improvements in survival, without benefits to motor function in patients with ALS. Despite significant clinical trial efforts to understand the genetic, epigenetic, and molecular pathways linked to ALS pathophysiology, therapeutic translation has remained disappointingly slow, probably due to the complexity and the heterogeneity of this disease. Many other drugs to tackle ALS have been tested for 20 years without any success. Dexpramipexole is a BTZ structural analog of riluzole and was a great hope for the treatment of ALS. In this review, as an interesting case study in the development of a new medicine to treat ALS, we present the strategy of the development of Dexpramipexole, which was one of the most promising drugs against ALS.