Catechol-O-methyltransferase (COMT) plays an important role in the termination of dopamine signaling in brain regions such as the prefrontal cortex and hippocampus, making it an important regulator of a number of cognitive and behavioral processes.  Therefore, central inhibition of COMT may be useful in the treatment of a variety of conditions associated with dysregulated cortical dopaminergic function like schizophrenia, ADHD, and traumatic brain injury. COMT has two isoforms encoded from the same gene—a membrane-bound form (MB-COMT) and a soluble form (S-COMT). Genetic and pharmacological studies have demonstrated that the membrane-bound form is especially important in the human brain. Though S-COMT expression predominates in the periphery, MB-COMT has higher expression in the brain. In addition, MB-COMT has a greater affinity for catechol substrates than S-COMT and is likely to metabolize catecholamines at the physiologically relevant concentrations found in the brain. The known brain penetrant COMT inhibitor tolcapone, a nitrocatechol structured compound, requires close liver monitoring due to idiosyncratic hepatoxcity thus preventing widespread use in psychiatric disorders.   Accordingly, we have developed potent and selective non-nitrocatechol COMT inhibitors based on the benzthiazole scaffold and evaluated their pharmacokinetic and brain penetration properties.    Small substituents at the 5-position of the benzthiazole were found to increase metabolic stability without sacrificing potency.  Compounds with good pharmacokinetics and low P-gp efflux ratios were identified; however, brain penetration was unexpectedly poor. An X-ray co-crystal structure of compound X in the S-COMT active site shows chelation of the active site magnesium similar to catechol-based inhibitors.

4-Hydroxybenzthiazole inhibitors of catechol-<i>O</i>-methyltransferase

2019 Spring National Meeting

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4-Hydroxybenzthiazole inhibitors of catechol-O-methyltransferase