Discovery of a Potent, Selective, and Blood-Brain Barrier Permeable Non-nitrocatechol Inhibitor of Catechol- O-methyltransferase

  • J Med Chem. 2024 Oct 24;67(20):18384-18399. doi: 10.1021/acs.jmedchem.4c01682.
Sofia Benfeito  1 ,  Bárbara Albuquerque  2  3 ,  Lisa Sequeira  1 ,  Carla Lima  1 ,  Daniel Chavarria  1 ,  Paula Serrão  2  3 ,  Fernando Cagide  1 ,  Patrício Soares-da-Silva  2  3 ,  Fernanda Borges  1
Affiliations
  • 1. CIQUP-IMS/Department of Chemistry and Biochemistry, Faculty of Sciences, University of Porto, Porto 4169-007, Portugal.
  • 2. Department of Biomedicine - Unit of Pharmacology and Therapeutics, Faculty of Medicine, University of Porto, Porto 4200-319, Portugal.
  • 3. MedInUP - Center for Drug Discovery and Innovative Medicines, University of Porto, Porto 4200-319, Portugal.
PMID: 39374514 DOI: 10.1021/acs.jmedchem.4c01682
Abstract

A new library of non-nitrocatechol compounds (HetCAMs) was developed and their efficacy was compared to tolcapone, a standard COMT Inhibitor for PD. Compound 9 emerged as the most potent inhibitor, showing selective inhibition of brain (IC50 = 24 nM) and liver (IC50 = 81 nM) MB-COMT over liver S-COMT (IC50 = 620 nM) isoforms. Although compound 9 presented higher IC50 values than tolcapone, it was more selective for brain MB-COMT than liver S-COMT. Unlike tolcapone, compound 9 is not a tight-binding inhibitor and is less cytotoxic to HepG2 and SK-N-SH cells. Additionally, compound 9 is predicted to cross the blood-brain barrier (BBB) by passive diffusion and chelate divalent metals like Fe(II) and Cu(II). The results demonstrate the potential of this rational drug design strategy for developing new CNS-active drug candidates, offering symptom relief via COMT inhibition that can provide a long-term, disease-modifying outcome (chelation of divalent metals) in PD.

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