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Levodopa, in association with a DOPA decarboxylase inhibitor (e.g., carbidopa or benserazide) has for many years been the undisputed gold standard drug for the symptomatic treatment of Parkinson’s disease (PD). However, given its rapid disposition and elimination in the periphery, it was hypothesized that significant enhancements in levodopa bioavailability and clinical efficacy could be achieved through co‐adjuvant therapy with a catechol‐O‐methyl‐transferase (COMT) inhibitor. Early attempts, dating back to the late 1950s, to discover COMT inhibitors were generally hampered by their lack of in vivo efficacy, target selectivity or by considerable toxicity. It was not until the late 1990s that entacapone and tolcapone, representatives of a new class of potent COMT inhibitors (nitrocatechol derivatives), made their way to clinical practice for the treatment of PD. Even though these drugs have since contributed to an increase in the usefulness of levodopa therapy, each of them presents known limitations, namely concerning their clinical efficacy and safety. The unmet medical need for more efficacious and safer COMT inhibitors has motivated intense research in this field over the last decade. Opicapone is the first, third‐generation COMT inhibitor among the nitrocatechol derivatives under clinical development, and demonstrates superior pharmacodynamic and safety profiles in humans, over previous drugs. In this chapter, we review the major advances in this field, summarize the relevant non‐clinical and clinical human pharmacology and discuss new insights into the mechanism of action of opicapone.

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