Liver says no: the ongoing search for safe catechol O-methyltransferase inhibitors to replace tolcapone

Autores da FMUP

• Maria Paula De Valadares Souto Pinto Serrão

  Autor

• Patrício Manuel Vieira Araújo Soares Da Silva

  Autor

Participantes de fora da FMUP

• Silva, TB
• Borges, M.

Unidades de investigação

• Biomedicina

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.

Copyright © 2020 Elsevier Ltd. All rights reserved.

Keywords

• METHYL TRANSFERASE; MOLECULAR-MECHANISMS; PARKINSONS-DISEASE; ENTACAPONE; TOXICITY; GENOTYPE; RISK; SCHIZOPHRENIA; DERIVATIVES; METABOLISM