Cheah Benjamin C, Kiernan Matthew C
Neuroscience Research Australia and Multi-disciplinary Amyotrophic Lateral Sclerosis Clinic, Prince of Wales Clinical School, University of New South Wales, Barker Street, Randwick, Sydney, NSW 2031, Australia.
IDrugs. 2010 Dec;13(12):911-20.
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.
右普拉克索（KNS-760704）是普拉克索的R(+)对映体，由Knopp神经科学公司和百健艾迪公司研发，作为肌萎缩侧索硬化症（ALS）一种普遍致命的神经退行性疾病的潜在神经保护疗法。普拉克索，仅为S(-)对映体，是一种非麦角多巴胺能自身受体激动剂，目前已上市用于治疗帕金森病和不宁腿综合征。有人提出普拉克索具有广泛的神经保护特性，主要通过抗氧化作用、抑制凋亡酶以及维持线粒体结构和活性来实现。最近的研究表明普拉克索具有抗兴奋性毒性特性，这增加了其对ALS患者产生有益作用的可能性。然而，普拉克索具有较高的内在多巴胺能受体活性，因此，包括体位性低血压和幻觉在内的剂量限制性副作用很常见。右普拉克索对多巴胺能受体的亲和力显著较低，因此不太可能与多巴胺能副作用相关。在迄今为止的临床试验中，右普拉克索在剂量高达帕金森病患者中普拉克索最大推荐日剂量67倍的情况下仍安全且耐受性良好，并已显示出神经保护益处的迹象。本报告总结了右普拉克索的化学和药理学特性，并描述了该药物在药物研发流程中的潜在用途。
