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Tozadenant or Preladenant or Vipadenant

Barbara Cacciari, Stephanie Federico, Giampiero Spalluto
In the past decades, many efforts were done to develope ligands for the adenosine receptors, with the purpose to individuate agonists and antagonists affine and selective for each subtypes , named A1, A2A, A2B, and A3. These intense studies allowed a deeper and deeper knowledge of the nature and, moreover, of the pathophysiological roles of all the adenosine receptor subtypes. In particular, the involvment of the A2A adenosine receptor subtype in some physiological mechanisms in the brain, that could be related to important diseases such as the Parkinson's disease, encouraged the research in this field...
April 22, 2018: Mini Reviews in Medicinal Chemistry
Gengyang Yuan, Tanner C Jankins, Christopher G Patrick, Phaethon Philbrook, Olivia Sears, Stephen Hatfield, Michail Sitkovsky, Neil Vasdev, Steven H Liang, Mary Jo Ondrechen, Michael P Pollastri, Graham B Jones
Antagonism of the adenosine A2A receptor on T cells blocks the hypoxia-adenosinergic pathway to promote tumor rejection. Using an in vivo immunoassay based on the Concanavalin A mouse model, a series of A2A antagonists were studied and identified preladenant as a potent lead compound for development. Molecular modeling was employed to assist drug design and subsequent synthesis of analogs and those of tozadenant, including fluorinated polyethylene glycol PEGylated derivatives. The efficacy of the analogs was evaluated using two in vitro functional bioassays, and compound 29 , a fluorinated triethylene glycol derivative of preladenant, was confirmed as a potential immunotherapeutic agent...
2017: International Journal of Medicinal Chemistry
Anne Michel, Jean-Marie Nicolas, Sarah Rose, Michael Jackson, Peter Colman, Willy Briône, David Sciberras, Pierandrea Muglia, Dieter K Scheller, Martin Citron, Patrick Downey
OBJECTIVE: Investigate a combination of two clinically tested drugs, the NR2B antagonist Radiprodil and the A2A antagonist Tozadenant in the MPTP-treated marmoset model of Parkinson's Disease (PD). BACKGROUND: In PD, there remains a need for the development of non-dopaminergic drugs to effectively treat the motor symptoms without the induction of L-Dopa-induced motor complications. METHODS: Clinically relevant doses of Radiprodil and Tozadenant were given both alone and in combination without the addition of L-Dopa, and the antiparkinsonian efficacy of the treatments was assessed in a primate model of PD...
2017: PloS One
Wai Kin D Ko, Qin Li, Long Yun Cheng, Micaela Morelli, Manolo Carta, Erwan Bezard
Eltoprazine, a serotonergic (5-HT)1A/B receptor agonist, is a potential treatment for L-DOPA-induced dyskinesia (LID) in Parkinson's disease (PD) but notably compromises the anti-parkinsonian effects of L-DOPA, as seen in rodent and monkey models of PD. Preladenant, a selective adenosine A2a receptor antagonist, mediates modest anti-parkinsonian effects in parkinsonian monkeys. In a recent investigation, combined eltoprazine and preladenant treatment with a sub-threshold dose of L-DOPA acutely attenuated dyskinesia without exacerbating PD disability in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated macaques...
July 21, 2017: European Journal of Pharmacology
Robert Fong, Suhail Khokhar, Atif N Chowdhury, Kelvin G Xie, Josiah Hiu-Yuen Wong, Aaron P Fox, Zheng Xie
Various studies have explored different ways to speed emergence from anesthesia. Previously, we have shown that three drugs that elevate intracellular cAMP (forskolin, theophylline, and caffeine) accelerate emergence from anesthesia in rats. However, our earlier studies left two main questions unanswered. First, were cAMP-elevating drugs effective at all anesthetic concentrations? Second, given that caffeine was the most effective of the drugs tested, why was caffeine more effective than forskolin since both drugs elevate cAMP? In our current study, emergence time from anesthesia was measured in adult rats exposed to 3% isoflurane for 60 min...
September 1, 2017: Journal of Neurophysiology
X Zhou, J Doorduin, P H Elsinga, R A J O Dierckx, E F J de Vries, C Casteels
Several lines of evidence imply alterations in adenosine signaling in Parkinson's disease (PD). Here, we investigated cerebral changes in adenosine 2A receptor (A2AR) availability in 6-hydroxydopamine (6-OHDA)-lesioned rats with and without levodopa-induced dyskinesia (LID) using positron-emission tomography (PET) with [(11)C]preladenant. In parallel dopamine type 2 receptor (D2R) imaging with [(11)C]raclopride PET and behavioral tests for motor and cognitive function were performed. METHODS: Parametric A2AR and D2R binding potential (BPND) images were reconstructed using reference tissue models with midbrain and cerebellum as reference tissue, respectively...
June 2, 2017: NeuroImage
Fabrizio Stocchi, Olivier Rascol, Robert A Hauser, Susan Huyck, Anjela Tzontcheva, Rachel Capece, Tony W Ho, Peter Sklar, Christopher Lines, David Michelson, David J Hewitt
OBJECTIVE: To evaluate the adenosine 2a receptor antagonist preladenant as a nondopaminergic drug for the treatment of Parkinson disease (PD) when given as monotherapy. METHODS: This was a randomized, 26-week, placebo- and active-controlled, parallel-group, multicenter, double-blind trial conducted in adults diagnosed with PD for <5 years who were not yet receiving l-dopa or dopamine agonists. Patients with a Unified Parkinson's Disease Rating Scale (UPDRS) part 3 (motor function) score ≥10 and Hoehn & Yahr score ≤3 were randomized 1:1:1:1:1 to preladenant 2, 5, or 10 mg twice daily, rasagiline 1 mg (active-control) once daily, or placebo...
June 6, 2017: Neurology
D Hesk, S Borges, R Dumpit, S Hendershot, D Koharski, P McNamara, S Ren, S Saluja, V Truong, K Voronin
MK 3814 is a potent and selective antagonist of the A2a receptor. A2a receptor antagonists have the potential for the treatment of Parkinson disease. Three distinct isotopically labelled forms of MK 3814 were synthesized. [3 H]MK 3814 was prepared for a preliminary absorption, distribution, metabolism, and excretion data (ADME) evaluation of the compound and [14 C]MK 3814 for more definitive ADME work, including an absorption, metabolism, and excretion study in man. In addition, [2 H4 ]MK 3814 was prepared as an internal standard for a liquid chromatography mass spectrometry bioanalytical method...
April 2017: Journal of Labelled Compounds & Radiopharmaceuticals
Xiaoyun Zhou, Ronald Boellaard, Kiichi Ishiwata, Muneyuki Sakata, Rudi A J O Dierckx, Johan R de Jong, Shingo Nishiyama, Hiroyuki Ohba, Hideo Tsukada, Erik F J de Vries, Philip H Elsinga
(11)C-preladenant was developed as a novel PET ligand for the adenosine A2A receptors (A2ARs). The present study aimed to evaluate the suitability of (11)C-preladenant PET for the quantification of striatal A2ARs and the assessment of A2AR occupancy in the conscious monkey brain. Methods:(11)C-preladenant was intravenously injected into conscious monkeys (n = 4, 18 PET scans), and a 91-min dynamic scan was started. Arterial blood samples in combination with metabolite analysis were obtained during the scan to provide the input function for kinetic modeling...
May 2017: Journal of Nuclear Medicine: Official Publication, Society of Nuclear Medicine
Nobutaka Hattori, Masashi Kikuchi, Noriaki Adachi, David Hewitt, Susan Huyck, Tadayuki Saito
BACKGROUND: Preladenant, an adenosine 2A antagonist, reduced daily OFF time when administered as adjunctive treatment in a previous phase 2 trial in non-Japanese Parkinson's disease (PD) patients on stable doses of levodopa. This study aimed to evaluate preladenant as adjunctive therapy in Japanese patients with PD. METHODS: In this randomized, placebo-controlled, double-blind, 12-week, dose-ranging, phase 2 study, Japanese patients with moderate to severe PD on a stable regimen of levodopa were randomly assigned 1:1:1:1 to preladenant 2 mg, 5 mg, or 10 mg BID or placebo...
November 2016: Parkinsonism & related Disorders
Wolfgang Oertel, Jörg B Schulz
Over a period of more than 50 years, the symptomatic treatment of the motor symptoms of Parkinson disease (PD) has been optimized using pharmacotherapy, deep brain stimulation, and physiotherapy. The arsenal of pharmacotherapies includes L-Dopa, several dopamine agonists, inhibitors of monoamine oxidase (MAO)-B and catechol-o-methyltransferase (COMT), and amantadine. In the later course of the disease, motor complications occur, at which stage different oral formulations of L-Dopa or dopamine agonists with long half-life, a transdermal application or parenteral pumps for continuous drug supply can be subscribed...
October 2016: Journal of Neurochemistry
Xiaoyun Zhou, Philip H Elsinga, Shivashankar Khanapur, Rudi A J O Dierckx, Erik F J de Vries, Johan R de Jong
PURPOSE: [11 C]Preladenant was developed as a novel adenosine A2A receptor PET radioligand. The aim of this study was to determine the radiation dosimetry of [11 C]preladenant and to investigate whether dosimetry estimation based on organ harvesting can be replaced by positron emission tomography (PET)/x-ray computed tomography (CT) imaging in rats. PROCEDURES: Male Wistar rats (n = 35) were i.v. injected with [11 C]preladenant. The tracer biodistribution was determined by organ harvesting at 1, 5, 15, 30, 60, and 90 min post injection...
April 2017: Molecular Imaging and Biology: MIB: the Official Publication of the Academy of Molecular Imaging
Valérie Mancel, François-Xavier Mathy, Pierre Boulanger, Stephen English, Marie Croft, Christopher Kenney, Tarra Knott, Armel Stockis, Massimo Bani
1. This phase-I study (NCT02240290) was designed to investigate the human absorption, disposition and mass balance of 14 C-tozadenant, a novel A2a receptor antagonist in clinical development for Parkinson s disease. 2. Six healthy male subjects received a single oral dose of tozadenant (240 mg containing 81.47 KBq of [14 C]-tozadenant). Blood, urine and feces were collected over 14 days. Radioactivity was determined by liquid scintillation counting or accelerator mass spectrometry (AMS). Tozadenant and metabolites were characterized using HPLC-MS/MS and HPLC-AMS with fraction collection...
August 2017: Xenobiotica; the Fate of Foreign Compounds in Biological Systems
Christine Vala, Thomas J Morley, Xuechun Zhang, Caroline Papin, Adriana Alexandre S Tavares, H Sharon Lee, Cristian Constantinescu, Olivier Barret, Vincent M Carroll, Ronald M Baldwin, Gilles D Tamagnan, David Alagille
Imaging agents that target adenosine type 2A (A2A ) receptors play an important role in evaluating new pharmaceuticals targeting these receptors, such as those currently being developed for the treatment of movement disorders like Parkinson's disease. They are also useful for monitoring progression and treatment efficacy by providing a noninvasive tool to map changes in A2A receptor density and function in neurodegenerative diseases. We previously described the successful evaluation of two A2A -specific radiotracers in both nonhuman primates and in subsequent human clinical trials: [(123) I]MNI-420 and [(18) F]MNI-444...
September 6, 2016: ChemMedChem
Xiaoyun Zhou, Shivashankar Khanapur, Johan R de Jong, Antoon Tm Willemsen, Rudi Ajo Dierckx, Philip H Elsinga, Erik Fj de Vries
[11 C]Preladenant was developed as a novel adenosine A2A receptor positron emission tomography radioligand. The present study aims to evaluate the suitability of [11 C]preladenant positron emission tomography for the quantification of striatal A2A receptor density and the assessment of striatal A2A receptor occupancy by KW-6002. Sixty- or ninety-minute dynamic positron emission tomography imaging was performed on rats. Tracer kinetics was quantified by the two-tissue compartment model, Logan graphical analysis and several reference tissue-based models...
February 2017: Journal of Cerebral Blood Flow and Metabolism
Annalisa Pinna, Wai Kin D Ko, Giulia Costa, Elisabetta Tronci, Camino Fidalgo, Nicola Simola, Qin Li, Mojgan Aghazadeh Tabrizi, Erwan Bezard, Manolo Carta, Micaela Morelli
BACKGROUND: The serotonin 5-HT1A/1B receptor agonist eltoprazine suppressed dyskinetic-like behavior in animal models of Parkinson's disease (PD) but simultaneously reduced levodopa (l-dopa)-induced motility. Moreover, adenosine A2A receptor antagonists, such as preladenant, significantly increased l-dopa efficacy in PD without exacerbating dyskinetic-like behavior. OBJECTIVES: We evaluated whether a combination of eltoprazine and preladenant may prevent or suppress l-dopa-induced dyskinesia, without impairing l-dopa's efficacy in relieving motor signs, in 2 PD models: unilateral 6-hydroxydopamine-lesioned rats and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated monkeys...
April 2016: Movement Disorders: Official Journal of the Movement Disorder Society
Robert A Hauser, Fabrizio Stocchi, Olivier Rascol, Susan B Huyck, Rachel Capece, Tony W Ho, Peter Sklar, Christopher Lines, David Michelson, David Hewitt
IMPORTANCE: Preladenant is an adenosine 2A receptor antagonist that reduced "off" time in a placebo-controlled phase 2b trial in patients with Parkinson disease (PD). We sought to confirm its efficacy in phase 3 trials. OBJECTIVE: To evaluate preladenant as an adjunct to levodopa in patients with PD and motor fluctuations. DESIGN, SETTING, AND PARTICIPANTS: Two 12-week, phase 3, randomized, placebo-controlled, double-blind trials performed from July 15, 2010, to April 16, 2013...
December 2015: JAMA Neurology
Anne Michel, Patrick Downey, Xavier Van Damme, Catherine De Wolf, Rainer Schwarting, Dieter Scheller
In Parkinson's disease (PD), dopaminergic therapies are often associated with the development of motor complications. Attention has therefore been focused on the use of non-dopaminergic drugs. This study developed a new behavioural method capable of demonstrating the added value of combining adenosinergic and glutamatergic receptor antagonists in unilateral 6-OHDA lesioned rats. Rats were dosed orally with Tozadenant, a selective A2A receptor antagonist, and three different doses of Radiprodil, an NR2B-selective NMDA receptor antagonist...
2015: PloS One
Olivier Rascol, Santiago Perez-Lloret, Joaquim J Ferreira
Levodopa (l-dopa)-induced motor complications, including motor fluctuations and dyskinesia, affect almost all patients with Parkinson's disease (PD) at some point during the disease course, with relevant implications in global health status. Various dopaminergic and nondopaminergic pharmacological approaches as well as more invasive strategies including devices and functional surgery are available to manage such complications. In spite of undisputable improvements during the last decades, many patients remain significantly disabled, and a fully satisfying management of l-dopa-induced motor complications is still an important unmet need of PD therapy...
September 15, 2015: Movement Disorders: Official Journal of the Movement Disorder Society
Mohamad Wessam Alnouri, Stephan Jepards, Alessandro Casari, Anke C Schiedel, Sonja Hinz, Christa E Müller
Adenosine receptors (ARs) have emerged as new drug targets. The majority of data on affinity/potency and selectivity of AR ligands described in the literature has been obtained for the human species. However, preclinical studies are mostly performed in mouse or rat, and standard AR agonists and antagonists are frequently used for studies in rodents without knowing their selectivity in the investigated species. In the present study, we selected a set of frequently used standard AR ligands, 8 agonists and 16 antagonists, and investigated them in radioligand binding studies at all four AR subtypes, A1, A2A, A2B, and A3, of three species, human, rat, and mouse...
September 2015: Purinergic Signalling
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