Preladenant, a selective adenosine A2A receptor antagonist, is not associated with QT/QTc prolongation

Wang, Z.; Xuan, Fengjuan; Lin, Wu; Troyer, Mattew; Tendolkar, Amol; Cutler, David L.

doi:10.1007/s00228-013-1541-5

Cited by 4 publications

(3 citation statements)

References 7 publications

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“…Finally, istradefylline and tozadenant, A 2A -AR antagonists, are new compounds used in patients to treat Morbus Parkinson (Hauser et al, 2014; Schapira et al, 2014; Adams et al, 2015). Their potential cardiac side effects have been partially studied in healthy volunteers (Wang et al, 2013). Other A 2A -AR antagonists have been studied clinically for treatment of melanoma (Adams et al, 2015).…”

Section: Discussionmentioning

confidence: 99%

Evidence for Arrhythmogenic Effects of A2A-Adenosine Receptors

et al. 2019

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Adenosine can be released from the heart and may stimulate four different cardiac adenosine receptors. A receptor subtype that couples to the generation of cyclic adenosine monophosphate (cAMP) is the A2A-adenosine receptor (A2A-AR). To better understand its role in cardiac function, we studied mechanical and electrophysiological effects in transgenic mice that overexpress the human A2A-AR in cardiomyocytes (A2A-TG). We used isolated preparations from the left atrium, the right atrium, isolated perfused hearts with surface electrocardiogram (ECG) recording, and surface body ECG recordings of living mice. The hypothesized arrhythmogenic effects of transgenicity per se and A2A-AR stimulation were studied. We noted an increase in the incidence of supraventricular and ventricular arrhythmias under these conditions in A2A-TG. Moreover, we noted that the A2A-AR agonist CGS 21680 exerted positive inotropic effect in isolated human electrically driven (1 Hz) right atrial trabeculae carneae. We conclude that A2A-ARs are functional not only in A2A-TG but also in isolated human atrial preparations. A2A-ARs in A2A-TG per se and their stimulation can lead to cardiac arrhythmias not only in isolated cardiac preparations from A2A-TG but also in living A2A-TG.

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Section: Discussionmentioning

confidence: 99%

Evidence for Arrhythmogenic Effects of A2A-Adenosine Receptors

et al. 2019

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“…266 A transient increase in systolic and diastolic blood pressure occurred after SCH420814 treatment, not associated with a delay of cardiac repolarization. 267 Preladenant showed good dose-dependent efficacy in vivo in the haloperidolinduced rat catalepsy assay and reversed the rat hypolocomotion induced by A 2A agonists. 28 Early clinical trials have been performed in PD patients where SCH420814, as mono-therapy or added to L-DOPA therapy, produced an improvement in motor function and a sustained efficacy in improving on-time and reducing off-time.…”

Section: Therapeutic Applications Of a 2a Antagonists In Clinical Trialsmentioning

confidence: 92%

“…Preclinical studies performed in different animal models reported a good safety profile and tolerability at different doses . A transient increase in systolic and diastolic blood pressure occurred after SCH420814 treatment, not associated with a delay of cardiac repolarization . Preladenant showed good dose‐dependent efficacy in vivo in the haloperidol‐induced rat catalepsy assay and reversed the rat hypolocomotion induced by A 2A agonists .…”

Section: Therapeutic Applications Of A2a Antagonists In Clinical Trialsmentioning

confidence: 96%

History and Perspectives of A_2AAdenosine Receptor Antagonists as Potential Therapeutic Agents

Preti

Baraldi

Moorman³

et al. 2015

Med. Res. Rev.

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Growing evidence emphasizes that the purine nucleoside adenosine plays an active role as a local regulator in different pathologies. Adenosine is a ubiquitous nucleoside involved in various physiological and pathological functions by stimulating A1 , A2A , A2B , and A3 adenosine receptors (ARs). At the present time, the role of A2A ARs is well known in physiological conditions and in a variety of pathologies, including inflammatory tissue damage and neurodegenerative disorders. In particular, the use of selective A2A antagonists has been reported to be potentially useful in the treatment of Parkinson's disease (PD). In this review, A2A AR signal transduction pathways, together with an analysis of the structure-activity relationships of A2A antagonists, and their corresponding pharmacological roles and therapeutic potential have been presented. The initial results from an emerging polypharmacological approach are also analyzed. This approach is based on the optimization of the affinity and/or functional activity of the examined compounds toward multiple targets, such as A1 /A2A ARs and monoamine oxidase-B (MAO-B), both closely implicated in the pathogenesis of PD.

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Adenosine A2A Receptor Antagonists in Parkinson’s Disease: Progress in Clinical Trials from the Newly Approved Istradefylline to Drugs in Early Development and Those Already Discontinued

2014

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Neurotransmitters other than dopamine, such as norepinephrine, 5-hydroxytryptamine, glutamate, adenosine and acetylcholine, are involved in Parkinson's disease (PD) and contribute to its symptomatology. Thus, the progress of non-dopaminergic therapies for PD has attracted much interest in recent years. Among new classes of drugs, adenosine A2A antagonists have emerged as promising candidates. The development of new highly selective adenosine A2A receptor antagonists, and their encouraging anti-parkinsonian responses in animal models of PD, has provided a rationale for clinical trials to evaluate the therapeutic potential and the safety of these agents in patients with PD. To date, the clinical research regarding A2A antagonists and their potential utilization in PD therapy continues to evolve between drugs just or previously discontinued (preladenant and vipadenant), new derivatives in development (tozadenant, PBF-509, ST1535, ST4206 and V81444) and the relatively old drug istradefylline, which has finally been licensed as an anti-parkinsonian drug in Japan. All these compounds have been shown to have a good safety profile and be well tolerated. Moreover, results from phase II and III trials also demonstrate that A2A antagonists are effective in reducing off-time, without worsening troublesome dyskinesia, and in increasing on-time with a mild increase of non-troublesome dyskinesia, in patients at an advanced stage of PD treated with L-DOPA. In addition, early findings suggest that A2A antagonists might also be efficacious as monotherapy in patients at an early stage of PD. This review summarizes pharmacological and clinical data available on istradefylline, tozadenant, PBF-509, ST1535, ST4206, V81444, preladenant and vipadenant.

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Preladenant, a selective adenosine A2A receptor antagonist, is not associated with QT/QTc prolongation

Abstract: At clinical and supratherapeutic doses, preladenant is not associated with QTc prolongation.

Cited by 4 publications

References 7 publications

Evidence for Arrhythmogenic Effects of A2A-Adenosine Receptors

Evidence for Arrhythmogenic Effects of A2A-Adenosine Receptors

History and Perspectives of A_2AAdenosine Receptor Antagonists as Potential Therapeutic Agents

Adenosine A2A Receptor Antagonists in Parkinson’s Disease: Progress in Clinical Trials from the Newly Approved Istradefylline to Drugs in Early Development and Those Already Discontinued

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Preladenant, a selective adenosine A2A receptor antagonist, is not associated with QT/QTc prolongation

Abstract: At clinical and supratherapeutic doses, preladenant is not associated with QTc prolongation.

Cited by 4 publications

References 7 publications

Evidence for Arrhythmogenic Effects of A2A-Adenosine Receptors

Evidence for Arrhythmogenic Effects of A2A-Adenosine Receptors

History and Perspectives of A2AAdenosine Receptor Antagonists as Potential Therapeutic Agents

Adenosine A2A Receptor Antagonists in Parkinson’s Disease: Progress in Clinical Trials from the Newly Approved Istradefylline to Drugs in Early Development and Those Already Discontinued

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History and Perspectives of A_2AAdenosine Receptor Antagonists as Potential Therapeutic Agents