Discovery of\na Potent, Selective, and Blood-Brain\nBarrier Permeable Non-nitrocatechol Inhibitor of Catechol‑<i>O</i>‑methyltransferase

A new library of non-nitrocatechol\ncompounds (HetCAMs)\nwas developed\nand their efficacy was compared to tolcapone, a standard COMT inhibitor\nfor PD. Compound <b>9</b> emerged as the most potent inhibitor,\nshowing selective inhibition of brain (IC<sub>50</sub> = 24 nM) and\nliver (IC<sub>50</sub> = 81 nM) MB-COMT over liver S-COMT (IC<sub>50</sub> = 620 nM) isoforms. Although compound <b>9</b> presented\nhigher IC<sub>50</sub> values than tolcapone, it was more selective\nfor brain MB-COMT than liver S-COMT. Unlike tolcapone, compound <b>9</b> is not a tight-binding inhibitor and is less cytotoxic to\nHepG2 and SK-N-SH cells. Additionally, compound <b>9</b> is\npredicted to cross the blood–brain barrier (BBB) by passive\ndiffusion and chelate divalent metals like Fe(II) and Cu(II). The\nresults demonstrate the potential of this rational drug design strategy\nfor developing new CNS-active drug candidates, offering symptom relief\nvia COMT inhibition that can provide a long-term, disease-modifying\noutcome (chelation of divalent metals) in PD.