- Development of blood-brain barrier permeable nitrocatechol-based catechol O-methyltransferase inhibitors with reduced potential for hepatotoxicity
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Recent efforts have been focused on the development of centrally active COMT inhibitors, which can be valuable assets for neurological disorders such as Parkinson's disease, due to the severe hepatotoxicity risk associated with tolcapone. New nitrocatechol COMT inhibitors based on naturally occurring caffeic acid and caffeic acid phenethyl ester were developed. All nitrocatechol derivatives displayed potent inhibition of peripheral and cerebral COMT within the nanomolar range. Druglike derivatives 13, 15, and 16 were predicted to cross the blood-brain barrier in vitro and were significantly less toxic than tolcapone and entacapone when incubated at 50 μM with rat primary hepatocytes. Moreover, their unique acidity and electrochemical properties decreased the chances of formation of reactive quinone-imines and, as such, the potential for hepatotoxicity. The binding mode of 16 confirmed that the major interactions with COMT were established via the nitrocatechol ring, allowing derivatization of the side chain for future lead optimization efforts.
- Silva, Tiago,Mohamed, Tarek,Shakeri, Arash,Rao, Praveen P.N.,Martínez-Gonzalez, Loreto,Pérez, Daniel I.,Martínez, Ana,Valente, Maria Jo?o,Garrido, Jorge,Uriarte, Eugenio,Serr?o, Paula,Soares-Da-silva, Patrício,Remi?o, Fernando,Borges, Fernanda
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p. 7584 - 7597
(2016/09/04)
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- Efficient approach to pure entacapone and related compounds
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A new and efficient process through a new intermediate, (2E)-2-cyano-3-(3,4-dihydroxy-5-nirtrophenyl)prop-2-enoic acid 15, has been described for preparing substantially pure entacapone 1. This new intermediate 15 was prepared by Knoevenagel condensation of 3,4-dihydroxy-5-nitrobenzaldehyde 2 with 2-cyanoacetic acid 14 and was further condensed with diethylamine to get pure entacapone 1. Some of the important process-related impurities of entacapone (17, 18, 19, and 20) were also prepared easily from this intermediate 15. Copyright Taylor & Francis Group, LLC.
- Srikanth,Ray, Uttam Kumar,Srinivas Rao,Gupta, P. Badarinadh,Lavanya,Islam, Aminul
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experimental part
p. 1359 - 1366
(2012/04/04)
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