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Development of Blood−Brain Barrier Permeable Nitrocatechol-Based Catechol O‑Methyltransferase Inhibitors with Reduced Potential for Hepatotoxicity

2016Journal article Restricted access
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dc.contributor.authorSilva, Tiago
dc.contributor.authorMohamed, Tarek
dc.contributor.authorShakeri, Arash
dc.contributor.authorRao, Praveen P. N.
dc.contributor.authorMartínez-González, Loreto
dc.contributor.authorPérez, Daniel I.
dc.contributor.authorMartínez, Ana
dc.contributor.authorValente, Maria João
dc.contributor.authorGarrido, Jorge
dc.contributor.authorUriarte, Eugenio
dc.contributor.authorSerrão, Paula
dc.contributor.authorSoares-da-Silva, Patrício
dc.contributor.authorRemião, Fernando
dc.contributor.authorBorges, Fernanda
dc.date.accessioned2017-06-29T10:28:27Z
dc.date.embargo2117
dc.date.issued2016
dc.description.abstractRecent 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.pt_PT
dc.description.versioninfo:eu-repo/semantics/publishedVersionpt_PT
dc.identifier.doi10.1021/acs.jmedchem.6b00666pt_PT
dc.identifier.urihttp://hdl.handle.net/10400.22/9964
dc.language.isoengpt_PT
dc.publisherAmerican Chemical Societypt_PT
dc.relation.ispartofseriesJournal of Medicinal Chemistry;Vol. 59, Issue 16
dc.relation.publisherversionhttp://pubs.acs.org/doi/abs/10.1021/acs.jmedchem.6b00666pt_PT
dc.titleDevelopment of Blood−Brain Barrier Permeable Nitrocatechol-Based Catechol O‑Methyltransferase Inhibitors with Reduced Potential for Hepatotoxicitypt_PT
dc.typejournal article
dspace.entity.typePublication
oaire.citation.titleJournal of Medicinal Chemistrypt_PT
person.familyNameGarrido
person.givenNameJorge
person.identifier.orcid0000-0001-8981-231X
person.identifier.scopus-author-id7202779733
rcaap.rightsclosedAccesspt_PT
rcaap.typearticlept_PT
relation.isAuthorOfPublicationf548e711-c68e-4c49-9471-9923c047116d
relation.isAuthorOfPublication.latestForDiscoveryf548e711-c68e-4c49-9471-9923c047116d

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