Design, synthesis and evaluation of 3-hydroxypyridin-4-ones as inhibitors of catechol-O-methyltransferase

Abstract

The most effective treatment of Parkinson’s disease is restoring central dopamine levels with levodopa, the metabolic precursor of dopamine. However, due to extensive peripheral metabolism by aromatic L-amino acid decarboxylase and catechol-O-methyltransferase (COMT), only a fraction of the levodopa dose reaches the brain unchanged. Thus, by preventing levodopa metabolism and increasing the availability of levodopa for uptake into the brain, the inhibition of COMT would be beneficial in Parkinson’s disease. Although nitrocatechol COMT inhibitors have been used in the treatment of Parkinson’s disease, efforts have been made to discover non-nitrocatechol inhibitors. In the present study, the 3-hydroxypyridin-4-one scaffold was selected for the design and synthesis of non-nitrocatechol COMT inhibitors since the COMT inhibitory potential of this class has been illustrated. Using COMT obtained from porcine liver, it was shown that a synthetic series of ten 3-hydroxypyridin-4-ones are in vitro inhibitors with IC50 values ranging from 4.55 to 19.8 µM. Although these compounds are not highly potent inhibitors, they may act as leads for the development of non-nitrocatechol COMT inhibitors. Such compounds would be appropriate for the treatment of Parkinson’s disease