Liver says no: the ongoing search for safe catechol O-methyltransferase inhibitors to replace tolcapone. Issue 10 (October 2020)

• Record Type: Journal Article
• Authors: Silva, Tiago Barros; Borges, Fernanda; Serrão, Maria Paula; Soares-da-Silva, Patrício
• Is Part Of: Drug discovery today. Volume 25:Issue 10(2020)
• Page Start: 1846
• Page End: 1854
• Publication Date: 2020-10
• Subjects: Drugs -- Design -- Periodicals; Drugs -- Research -- Periodicals; 615.1
• DOI: 10.1016/j.drudis.2020.07.015
• Languages: English
• ISSNs: 1359-6446

Abstract

Highlights: COMT inhibitors are valuable tools to help restore the dopamine pool in the brain. Clinically relevant COMT inhibitors are tight-binding nitrocatechols. Alternative non-nitrocatechol COMT inhibitors decrease the risk of drug-induced liver damage. Non-nitrocatechol COMT inhibitors can specifically target the cerebral isoform of COMT. Abstract : Catechol O -methyltransferase (COMT) inhibitors are valuable co-adjuvant drugs in the clinical management of Parkinson's disease (PD), and recent data also suggest therapeutic benefits in other neurological disorders associated with dopamine depletion. However, the relationship between tolcapone administration with fatal cases of drug-induced liver damage gave COMT inhibitors a bad reputation as hepatotoxic drugs. Thus, there is a pressing need to feed the pipeline with safe COMT inhibitors to replace tolcapone, the only currently available COMT inhibitor that effectively reaches the brain. Recent efforts led to promising phenolic and nonphenolic COMT inhibitors, which allow isoform-specific targeting and avoid the toxicological and pharmacokinetic (PK) shortcomings of classic nitrocatechols. Here, we describe advances made in this field over the past 5 years.