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

A new library of non-nitrocatechol compounds (HetCAMs) was developed and their efficacy was compared to tolcapone, a standard COMT inhibitor for PD. Compound <b>9</b> 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 <b>9</b> presented higher IC₅₀ values than tolcapone, it was more selective for brain MB-COMT than liver S-COMT. Unlike tolcapone, compound <b>9</b> is not a tight-binding inhibitor and is less cytotoxic to HepG2 and SK-N-SH cells. Additionally, compound <b>9</b> 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.