The challenge of developing adenosine A2A antagonists for Parkinson disease: Istradefylline, preladenant, and tozadenant

International Union of Basic and Clinical Pharmacology. CXII: Adenosine Receptors: A Further Update

“…The nonxanthine A 2A AR antagonist preladenant (21, SCH-420814) is one of the most potent and selective A 2A AR antagonists. It has been evaluated in clinical trials for PD and was found to be well tolerated but did not show significant beneficial effects (Stocchi et al, 2017; LeWitt et al, 2020 ). As observed with istradefylline, the study design is most critical for these types of clinical PD studies and may have contributed to the negative outcome in the case of preladenant ( Hauser et al, 2015 ).…”

The Pharmacological Potential of Adenosine A2A Receptor Antagonists for Treating Parkinson’s Disease

“…Taken along with the evidence from animal models of PD, an improvement of motor disability would be predicted when adenosine A 2A antagonists are used in combination with levodopa therapy [ 32 , 91 ]. Not surprisingly, a number of selective adenosine A 2A receptor antagonists have been developed [ 92 ] with the aim of increasing the duration of motor improvement seen during the time when symptoms are adequately controlled by medication (ON time) and decreasing the periods of inadequate control of PD symptoms (OFF time) in patients receiving levodopa but where insufficient efficacy is occurring [ 18 , 32 , 93 ]. Surprisingly, however, clinical development has proved challenging.…”

“…Two candidate molecules, vipadenant and BIIB 014, have undergone only limited human testing [ 94 , 95 , 96 ], with vipadenant development discontinued due to toxicological concerns. Three other compounds—istradefylline [ 97 , 98 , 99 , 100 , 101 , 102 , 103 , 104 ], preladenant [ 105 , 106 ] and tozadenant [ 107 ]—have been examined in phase II and phase III clinical trials, and while positive efficacy results were obtained in all phase II studies, tozadenant was discontinued due to toxicity concerns [ 108 ], and only istradefylline has successfully reached commercialization [ 18 ]. To date, istradefylline has received approval in the US and Japan for the treatment of adult PD patients experiencing OFF time who are currently taking levodopa (plus a decarboxylase inhibitor) [ 109 , 110 ].…”

“…There are many reasons why the clinical studies of istradefylline and other adenosine antagonists has been challenging—for example, trial design, trial population selection, placebo effects—and these have been discussed these in detail elsewhere [ 18 , 19 ]. The concepts of ON and OFF time and other motor endpoints are tailored to reflect the effects of dopaminergic replacement therapy, and there are no clinical endpoints available that fully capture the effects of non-dopaminergic approaches.…”

“…Adenosine receptors are widely expressed throughout the central nervous system and peripheral tissues or cells (for recent reviews, see Chen, 2014 [ 7 ]; Mori 2021 [ 10 ]) [ 7 , 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 ]. They belong to the family of G protein-coupled receptors (GPCRs), which possess seven transmembrane alpha helices, with three intracellular loops and three extracellular loops [ 11 , 21 ].…”