Medicinal Chemistry of CatecholO-Methyltransferase (COMT) Inhibitors and Their Therapeutic Utility

Catechol O-methyltransferase (COMT) is the enzyme responsible for the O-methylation of endogenous neurotransmitters and of xenobiotic substances and hormones incorporating catecholic structures. COMT is a druggable biological target for the treatment of various central and peripheral nervous system disorders, including Parkinson's disease, depression, schizophrenia, and other dopamine deficiency-related diseases. The purpose of this perspective is fourfold: (i) to summarize the physiological role of COMT inhibitors in central and peripheral nervous system disorders; (ii) to provide the history and perspective of the medicinal chemistry behind the discovery and development of COMT inhibitors; (iii) to discuss how the physicochemical properties of recognized COMT inhibitors are understood to exert influence over their pharmacological properties; and (iv) to evaluate the clinical benefits of the most relevant COMT inhibitors.