1000933-89-0Relevant articles and documents
Optimization of 8-Hydroxyquinolines as Inhibitors of Catechol O-Methyltransferase
Buchler, Ingrid,Akuma, Daniel,Au, Vinh,Carr, Gregory,De León, Pablo,Depasquale, Michael,Ernst, Glen,Huang, Yifang,Kimos, Martha,Kolobova, Anna,Poslusney, Michael,Wei, Huijun,Swinnen, Dominique,Montel, Florian,Moureau, Florence,Jigorel, Emilie,Schulze, Monika-Sarah E. D.,Wood, Martyn,Barrow, James C.
, p. 9647 - 9665 (2018)
A series of 8-hydroxy quinolines were identified as potent inhibitors of catechol O-methyltransferase (COMT) with selectivity for the membrane-bound form of the enzyme. Small substituents at the 7-position of the quinoline were found to increase metabolic stability without sacrificing potency. Compounds with good pharmacokinetics and brain penetration were identified and demonstrated in vivo modulation of dopamine metabolites in the brain. An X-ray cocrystal structure of compound 21 in the S-COMT active site shows chelation of the active site magnesium similar to catechol-based inhibitors. These compounds should prove useful for treatment of many neurological and psychiatric conditions associated with compromised cortical dopamine signaling.
COMT INHIBITING METHODS AND COMPOSITIONS
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Paragraph 0112, (2016/08/23)
The present inventions include a method of inhibiting COMT enzyme in a subject as well as compounds of formula (I), or a pharmaceutically acceptable salt thereof, that are useful in the treatment of various disorders mediated by COMT, including Parkinson's disease and/or schizophrenia.
