Current Opinion in Investigational Drugs

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24 Current Opinion in Investigational Drugs 2006 Vol 7 No 1 10. Yang Y, Li Q, Shuaib A: Neuroprotection by 2-h postischemia administration of two free radical scavengers, α-phenyl-N-tert-butylnitrone (PBN) and N-tert-butyl-(2-sulfophenyl)-nitrone (S-PBN), in rats subjected to focal embolic cerebral ischemia. Exp Neurol (2000) 163(1):39-45. 11. Thomas CE, Ohlweiler DF, Carr AA, Nieduzak TR, Hay DA, Adams G, Vaz R, Bernotas RC: Characterization of the radical trapping activity of a novel series of cyclic nitrone spin traps. J Biol Chem (1996) 271(6):3097- 3104. 12. Johnson MP, McCarty DR, Velayo NL, Markgraf CG, Chmielewski PA, Ficorilli JV, Cheng HC, Thomas CE: MDL 101,002, a free radical spin trap, is efficacious in permanent and transient focal ischemia models. Life Sci (1998) 63(4):241-253. 13. Dhainaut A, Tizot A, Raimbaud E, Lockhart B, Lestage P, Goldstein S: Synthesis, structure, and neuroprotective properties of novel imidazolyl nitrones. J Med Chem (2000) 43(11):2165-2175. 14. Lockhart B, Roger A, Bonhomme N, Goldstein S, Lestage P: In vivo neuroprotective effects of the novel imidazolyl nitrone free-radical scavenger (Z)-α-[(2-thiazol-2-yl)imidazole-4-yl]-N-tert-butylnitrone (S34176). Eur J Pharmacol (2005) 511(2-3):127-136. 15. Green AR, Ashwood T, Odergren T, Jackson DM: Nitrones as neuroprotective agents in cerebral ischemia with particular reference to NXY-059. Pharmacol Ther (2003) 100(3):195-214. 16. Kuroda S, Tsuchidate R, Smith ML, Maples KR, Siesjo BK: Neuroprotective effects of a novel nitrone, NXY-059, after transient focal cerebral ischemia in the rat. J Cereb Blood Flow Metab (1999) 19(7):778-787. 17. Sydserff SG, Borelli AR, Green AR, Cross AJ: Effect of NXY-059 on infarct volume after transient or permanent middle cerebral artery occlusion in the rat; studies on dose, plasma concentration and therapeutic time window. Br J Pharmacol (2002) 135(1):103-112. 18. Zhao Z, Cheng M, Maples KR, Ma JY, Buchan AM: NXY-059, a novel free radical trapping compound, reduces cortical infarction after permanent focal ischemia in the rat. Brain Res (2001) 909(1-2):46-50. 19. Marshall JW, Duffin KJ, Green AR, Ridley RM: NXY-059, a free radicaltrapping agent, substantially lessens the functional disability resulting from cerebral ischemia in primate species. Stroke (2001) 32(1):190-198. 20. Marshall JW, Cummings RM, Bowes LJ, Ridley RM, Green AR: Functional and histological evidence for the protective effect of NXY-059 in a primate model of stroke when given 4 hours after occlusion. Stroke (2003) 34(9):2228-2233. • This paper describes the efficacy of NXY-059 in a monkey model of stroke. 21. Lyden P, Shauib A, Ng K, Levin K, Atkinson RP, Rajput A, Wechsler L, Ashwood T, Claesson L, Odergren T, Salazar-Grueso E: Clomethiazole acute stroke study in ischemic stroke (CLASS-I): Final results. Stroke (2002) 33(1):122-128. 22. Diener HC, AlKhedr A, Busse O, Hacke W, Zingmark PH, Jonsson N, Basun H: Treatment of acute ischaemic stroke with the low-affinity, usedependent NMDA antagonist AR-R15896AR. A safety and tolerability study. J Neurol (2002) 249(5):561-568. 23. Marshall JW, Green AR, Ridley RM: Comparison of the neuroprotective effect of clomethiazole, AR-R15896AR and NXY-059 in a primate model of stroke using histological and behavioural measures. Brain Res (2003) 972(1-2):119-126. 24. Lapchak PA, Araujo DM, Song D, Wei J, Zivin JA: Neuroprotective effects of the spin trap agent disodium-[(tert-butylimino)methyl]benzene-1,3disulfonate N-oxide (generic NXY-059) in a rabbit small clot embolic stroke model - combination studies with the thrombolytic tissue plasminogen activator. Stroke (2002) 33(5):1411-1415. 25. Lapchak PA, Song D, Wei J, Zivin JA: Coadministration of NXY-059 and tenecteplase six hours following embolic strokes in rabbits improved clinical rating scores. Exp Neurol (2004) 188(2):279-285. 26. Dehouck MP, Cecchelli R, Richard Green A, Renftel M, Lundquist S: In vitro blood-brain barrier permeability and cerebral endothelial cell uptake of the neuroprotective nitrone compound NXY-059 in normoxic, hypoxic and ischemic conditions. Brain Res (2002) 955 (1-2):229-235. 27. Han M, He QP, Yong G, Siesjo BK, Li PA: NXY-059, a nitrone with free radical trapping properties inhibits release of cytochrome C after cerebral ischemia. Cell Mol Biol (Noisy-le-grand) (2003) 49(8):1249-1252. 28. Edenius C, Strid S, Breitholtz-Emanuelsson A, Dalin L, Jerling M, Fransson B: NXY-059, the first nitrone being developed for stroke, is safe and well tolerated in young and elderly healthy volunteers. Cerebrovasc Dis (1999) 9:102. 29. Strid S, Borga O, Edenius C, Jostell KG, Odergren T, Weil A: Pharmacokinetics in renally impaired subjects of NXY-059, a nitrone-based, free-radical trapping agent developed for the treatment of acute stoke. Eur J Clin Pharmacol (2002) 58(6):409-415. 30. Lees KR, Sharma AK, Barer D, Ford GA, Kostulas V, Cheng Y-F, Odergren T: Tolerability and pharmacokinetics of the nitrone NXY-059 in patients with acute stroke. Stroke (2001) 32(3):675-680. 31. Lees KR, Barer D, Ford GA, Hacke W, Kostulas V, Sharma AK, Odegren T: Tolerability of NXY-059 at higher target concentrations in patients with acute stroke. Stroke (2003) 34(2):482-487. 32. Renovis Inc: Phase III trials for CEROVIVE (NXY-059) will continue as planned following interim data analysis. Press Release (2004): October 14. 33. AstraZeneca plc: First results from SAINT-1 trial show AstraZeneca's CEROVIVE (NXY-059) demonstrates a reduction in disability in patients with acute ischemia stroke. Press Release (2005):May 04. 34. Althaus JS, Fleck TJ, Becker DA, Hall ED, Vonvoigtlander PF: Azulenyl nitrones: Colorimetric detection of oxyradical end products and neuroprotection in the gerbil transient forebrain ischemia/reperfusion model. Free Radic Biol Med (1998) 24(5):738-744. 35. Klivenyi P, Matthews RT, Wermer M, Yang L, MacGarvey U, Becker DA, Natero R, Beal MF: Azulenyl nitrone spin trap protects against MPTP neurotoxicity. Exp Neurol (1998) 152(1):163-166. • This paper describes the neuroprotective effect of azulenyl nitrones in an animal model of Parkinson's disease. 36. Becker DA, Ley JJ, Echegoyen L, Alvarado R: Stilbazulenyl nitrone (STAZN): A nitronyl-substituted hydrocarbon with the potency of classical phenolic chain-breaking antioxidants. J Am Chem Soc (2002) 124(17):4678-4684. • This study demonstrated that STAZN has higher antioxidant activity than PBN and NXY-059. 37. Belayev L, Becker DA, Alonso OF, Liu Y, Busto R, Ley JJ, Ginsberg MD: Stilbazulenyl nitrone, a novel azulenyl nitrone antioxidant: Improved neurological deficit and reduced contusion size after traumatic brain injury in rats. J Neurosurg (2002) 96(6):1077-1083. • This study demonstrated the neuroprotective effect of STAZN in an animal model of traumatic brain injury. 38. Yang L, Calingasan NY, Chen J, Ley JJ, Becker DA, Beal MF: A novel azulenyl nitrone antioxidant protects against MPTP and 3nitropropionic acid neurotoxicities. Exp Neurol (2005) 191(1):86-93. • This study demonstrated the neuroprotective effect of STAZN in an animal model of Huntington's disease. 39. Ginsberg MD, Becker DA, Busto R, Belayev A, Zhang Y, Khoutorova L, Ley JJ, Zhao W, Belayev L: Stilbazulenyl nitrone, a novel antioxidant, is highly neuroprotective in focal ischemia. Ann Neurol (2003) 54(3):330-342. •• This paper describes the neuroprotective effect of STAZN in an animal model of ischemic stroke. 40. Ley JJ, Vigdorchik A, Belayev K, Zhao W, Busto R, Khoutorova L, Becker DA, Ginsberg MD: Stilbazulenyl nitrone, a second-generation azulenyl nitrone antioxidant, confers enduring neuroprotection in experimental focal cerebral ischemia in the rat: Neurobehavior, histopathology, and pharmacokinetics. J Pharmacol Exp Ther (2005) 313(3):1090-1100.
Drugs in development for Parkinson's disease: An update Tom H Johnston 1 & Jonathan M Brotchie 1,2 * Addresses 1 Toronto Western Research Institute Toronto Western Hospital University Health Network 399 Bathurst Street, MC 11-419 Toronto ON M5T 2S8 Canada Email: brotchie@uhnres.utoronto.ca 2Atuka Ltd 37th Floor First Canadian Place 100 King Street West Toronto ON M5X 1C9 Canada *To whom correspondence should be addressed Current Opinion in Investigational Drugs 2006 7(1):25-32 © The Thomson Corporation ISSN 1472-4472 The current development of emerging pharmacological treatments for Parkinson's disease (PD), from preclinical to launch, is summarized. Advances over the past year are highlighted, including the significant progress of several drugs through various stages of development. Several agents have been discontinued from development, either because of adverse effects or lack of clinical efficacy. The methyl-esterified form of L-DOPA (melevodopa) and the monoamine oxidase type B inhibitor rasagiline have both been launched. With regard to the monoamine re-uptake inhibitors, many changes have been witnessed, with new agents reaching preclinical development and pre-existing ones being discontinued or having no development reported. Of the dopamine agonists, many continue to progress successfully through clinical trials. Others have struggled to demonstrate a significant advantage over currently available treatments and have been discontinued. The field of non-dopaminergic treatments remains dynamic. The α2 adrenergic receptor antagonists and the adenosine A2A receptor antagonists remain in clinical trials. Trials of the neuronal synchronization modulator levetiracetam are at an advanced stage, and there has also been a new addition to the class (ie, seletracetam). There has been a change in the landscape of neuroprotective agents that modulate disease progression. Candidates from the classes of growth factors and glyceraldehyde-3-phosphate dehydrogenase inhibitors have been discontinued, or no development has been reported, and the mixed lineage kinase inhibitor CEP-1347 has been discontinued for PD treatment. Other drugs in this field, such as neuroimmunophilins, estrogens and α-synuclein oligomerization inhibitors, remain in development. Keywords Adenosine A2A, antiparkinsonian, monoamine oxidase inhibitors, non-dopaminergic Introduction A summary of select antiparkinsonian, antidyskinetic and neuroprotective/neurorestorative agents discussed in this review is presented in Tables 1 to 3. For a detailed discussion of the rationale for the majority of drugs in development, refer to our original review [1]. It should be 25 noted that, for commercial reasons, much of the information that relates to the development of these compounds is not available in the public domain and our understanding is derived from a variety of media reports of varying levels of reliability (eg, scientific literature, websites and company annual reports). Antiparkinsonian symptomatic agents In the field of antiparkinsonian therapies, the development of two dopamine-replacing compounds, etilevodopa and sumanirole, has been discontinued [2,3]. In both instances, it seems that this was not due to a lack of antiparkinsonian efficacy, but rather because of a lack of any advantage over competing products. The discontinuation of Pfizer's sumanirole is disappointing because it represented the first truly dopamine D2-selective agonist [4], and thus had great promise as an agent that might avoid some of the complications that are associated with traditional dopamine replacement therapy, such as dyskinesia and psychosis [5]. The reason behind the failure is unclear, and the entirety of Pfizer's preclinical data on this agent may never enter the public domain. However, from what has been made public, it appears that the preclinical investigations to define the advantageous properties of sumanirole over its competitors, especially with respect to development/ expression of dyskinesia and/or psychosis, were quite limited. This was particularly so in studies in 1-methyl-4-phenyl-1,2,3,6tetrahydropyridine (MPTP) primates, where little beyond antiparkinsonian efficacy appears to have been presented publicly [6,7]. Clinical trials designed to maximize the potential advantages of sumanirole might thus have been overlooked. Another significant change in the field within the last year is the decline in optimism regarding monoamine uptake inhibitors. Although the concept of enhancing remaining levels of dopamine with such compounds was supported by studies in MPTP-lesioned marmosets [8,9], the development of brasofensine, SPD-473 and SPD-451 has been discontinued [10]. The reasons behind these failures vary, but include, for example, lack of efficacy (SPD-473) [11]. In light of these developments, the results of the ongoing phase II trial of NS-2330 (NeuroSearch A/S/Boehringer Ingleheim Corp) [12] and the development of SEP-226330 (Sepracor Inc), an agent claimed to reduce dopamine and noradrenaline, but not serotonin, re-uptake, are awaited with interest [13]. Advances in the development of patch and controlledrelease formulations of agonists have been made. Leading the way are studies with the rotigotine patch (Schwarz Pharma AG/Otsuka Pharmaceutical Co Ltd), which is at the pre-registration stage, while the lisuride transcutaneous patch (Neurobiotec GmbH/Prestwick Pharmaceuticals Inc) has advanced to phase III clinical trials [14]. A controlledrelease version of the D2 agonist ropinirole (GlaxoSmithKline plc/SkyePharma plc) is undergoing phase III clinical trials [15].
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