The story of istradefylline-the first approved A2A antagonist for the treatment of parkinson's disease

Abstract

Istradefylline is the first selective adenosine A2A receptor antagonist which has recently been approved in Japan for Parkinson's disease therapy. Its launch followed a journey through drug development over a period of more than 20 years. This chapter details the progression of istradefylline from identification of the receptor target for Parkinson's disease therapy, to characterisation as a development candidate, to elucidation of its mechanism of action, and finally, to progression through clinical evaluation and eventual registration. Initially, istradefylline was shown to be a highly selective antagonist for adenosine A2A receptors and to have a highly localised site of action linked to the indirect output pathway from the striatum. Subsequently, it was found to be effective at reversing motor impairments in rodent and primate models of Parkinson's disease without provoking dyskinesia in primates. In clinical trials, istradefylline (as an adjunct to L-DOPA therapy) decreased 'OFF' time without increasing troublesome dyskinesia. The latter findings were the basis for its registration as a treatment for 'wearing off' in Parkinson's disease. However, this sequence of apparently logical events was interrupted by many challenges that had to be overcome-the topic of a still unfolding story. At this time, the development of istradefylline in Parkinson's disease is still incomplete and under further clinical investigation. Recently, the drug has shown effectiveness in experimental models of non-motor features of Parkinson's disease. The latter findings and further experience from the clinical use of istradefylline in Parkinson's disease will provide future scope for the development of A2A antagonists in treating human disorders.