The chemistry of catechol-O-methyltransferase inhibitors.

Despite several drawbacks, levodopa (L-dopa) remains the gold standard drug for treatment of the symptoms of Parkinson's disease (PD). L-dopa is a pro-drug of dopamine and is used to elevate striatal levels of the neurotransmitter. One approach to provide a more continuous and sustained delivery of dopamine has targeted one of the principal enzymes responsible for metabolic deactivation of L-dopa, namely catechol-O-methyltransferase (COMT). The chapter will provide a perspective of the medicinal chemistry behind the discovery of several COMT inhibitors and discuss how certain physicochemical parameters, including aqueous solubility and lipophilicity, are thought to influence pharmacokinetic properties such as absorption, distribution, and bioavailability.