Medicinal Chemistry of Catechol O‑Methyltransferase (COMT) Inhibitors and Their Therapeutic Utility

• Published in: Journal of medicinal chemistry 2014-11, Vol.57 (21), p.8692-8717
• Main Authors: Kiss, László E, Soares-da-Silva, Patrício
• Format: Article
• Language: English
• Subjects: Acetophenones - therapeutic use; Animals; Catalysis; Catechol O-Methyltransferase - metabolism; Catechol O-Methyltransferase Inhibitors - pharmacokinetics; Catechol O-Methyltransferase Inhibitors - therapeutic use; Catechols - therapeutic use; Clinical Trials as Topic; Crystallography, X-Ray; Humans; Inhibitory Concentration 50; Levodopa - metabolism; Male; Models, Molecular; Nitriles - therapeutic use; Oxadiazoles - therapeutic use; Parkinson Disease - drug therapy; Prodrugs - chemical synthesis; Prodrugs - chemistry; Rats
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm500572b

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.