Key result
3-Hydroxy-4-pyridinones and 5-hydroxy-4-pyrimidinones exhibited potent COMT inhibition and an improved toxicity profile compared to the marketed inhibitors tolcapone and entacapone.
Novel heterocyclic catechol mimics demonstrate potent COMT inhibition with improved toxicity profiles and a distinct binding mechanism compared to existing therapies.
May support safer COMT inhibitor development; animal data leave open human translation.
3-Hydroxy-4-pyridinones and 5-hydroxy-4-pyrimidinones were identified as inhibitors of catechol-O-methyltransferase (COMT) in a high-throughput screen. These heterocyclic catechol mimics exhibit potent inhibition of the enzyme and an improved toxicity profile versus the marketed nitrocatechol inhibitors tolcapone and entacapone. Optimization of the series was aided by X-ray cocrystal structures of the novel inhibitors in complex with COMT and cofactors SAM and Mg(2+). The crystal structures suggest a mechanism of inhibition for these heterocyclic inhibitors distinct from previously disclosed COMT inhibitors.
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Harrison et al. (2015) studied this question. 3-Hydroxy-4-pyridinones and 5-hydroxy-4-pyrimidinones vs. tolcapone and entacapone was evaluated on COMT inhibition and toxicity profile. 3-Hydroxy-4-pyridinones and 5-hydroxy-4-pyrimidinones exhibited potent COMT inhibition and an improved toxicity profile compared to the marketed inhibitors tolcapone and entacapone.
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