Utilize este identificador para referenciar este registo: http://hdl.handle.net/10400.22/9964
Título: Development of Blood−Brain Barrier Permeable Nitrocatechol-Based Catechol O‑Methyltransferase Inhibitors with Reduced Potential for Hepatotoxicity
Autor: Silva, Tiago
Mohamed, Tarek
Shakeri, Arash
Rao, Praveen P. N.
Martínez-González, Loreto
Pérez, Daniel I.
Martínez, Ana
Valente, Maria João
Garrido, Jorge
Uriarte, Eugenio
Serrão, Paula
Soares-da-Silva, Patrício
Remião, Fernando
Borges, Fernanda
Data: 2016
Editora: American Chemical Society
Relatório da Série N.º: Journal of Medicinal Chemistry;Vol. 59, Issue 16
Resumo: 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.
URI: http://hdl.handle.net/10400.22/9964
DOI: 10.1021/acs.jmedchem.6b00666
Versão do Editor: http://pubs.acs.org/doi/abs/10.1021/acs.jmedchem.6b00666
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