title: Development of Blood-Brain Barrier Permeable Nitrocatechol-Based Catechol O-Methyltransferase Inhibitors with Reduced Potential for Hepatotoxicity.
abstract: 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.
authors.affiliation: CIQ/Department of Chemistry and Biochemistry, Faculty of Sciences, University of Porto , Rua do Campo Alegre s/n, 4169-007 Porto, Portugal.
authors.forename: Tiago
authors.initials: T
authors.lastname: Silva
authors.affiliation: School of Pharmacy, Health Sciences Campus, University of Waterloo , 200 University Avenue West, Waterloo, Ontario N2L 3G1, Canada.
authors.forename: Tarek
authors.initials: T
authors.lastname: Mohamed
authors.affiliation: School of Pharmacy, Health Sciences Campus, University of Waterloo , 200 University Avenue West, Waterloo, Ontario N2L 3G1, Canada.
authors.forename: Arash
authors.initials: A
authors.lastname: Shakeri
authors.affiliation: School of Pharmacy, Health Sciences Campus, University of Waterloo , 200 University Avenue West, Waterloo, Ontario N2L 3G1, Canada.
authors.forename: Praveen P N
authors.initials: PP
authors.lastname: Rao
authors.affiliation: Centro de Investigaciónes Biológicas, CSIC, C/Ramiro de Maeztu, 28040 Madrid, Spain.
authors.forename: Loreto
authors.initials: L
authors.lastname: Martínez-González
authors.affiliation: Centro de Investigaciónes Biológicas, CSIC, C/Ramiro de Maeztu, 28040 Madrid, Spain.
authors.forename: Daniel I
authors.initials: DI
authors.lastname: Pérez
authors.affiliation: Centro de Investigaciónes Biológicas, CSIC, C/Ramiro de Maeztu, 28040 Madrid, Spain.
authors.forename: Ana
authors.initials: A
authors.lastname: Martínez
authors.affiliation: Laboratory of Toxicology, Department of Biological Sciences, Faculty of Pharmacy, UCIBIO-REQUIMTE , Rua de Jorge Viterbo Ferreira, 4050-313 Porto, Portugal.
authors.forename: Maria João
authors.initials: MJ
authors.lastname: Valente
authors.affiliation: Departamento de Engenharia Química, Instituto Superior de Engenharia do Porto (ISEP), Instituto Politécnico Porto , 4200-072 Porto, Portugal.
authors.forename: Jorge
authors.initials: J
authors.lastname: Garrido
authors.affiliation: Department of Organic Chemistry, Faculty of Pharmacy, University of Santiago de Compostela , 15782 Santiago de Compostela, Spain.
authors.forename: Eugenio
authors.initials: E
authors.lastname: Uriarte
authors.affiliation: Department of Pharmacology and Therapeutics, Faculty of Medicine, University of Porto , 4200-319 Porto, Portugal.|MedInUP-Center for Drug Discovery and Innovative Medicines, University of Porto, 4200-319, Porto, Portugal.
authors.forename: Paula
authors.initials: P
authors.lastname: Serrão
authors.affiliation: Department of Pharmacology and Therapeutics, Faculty of Medicine, University of Porto , 4200-319 Porto, Portugal.|MedInUP-Center for Drug Discovery and Innovative Medicines, University of Porto, 4200-319, Porto, Portugal.
authors.forename: Patrício
authors.initials: P
authors.lastname: Soares-da-Silva
authors.affiliation: Laboratory of Toxicology, Department of Biological Sciences, Faculty of Pharmacy, UCIBIO-REQUIMTE , Rua de Jorge Viterbo Ferreira, 4050-313 Porto, Portugal.
authors.forename: Fernando
authors.initials: F
authors.lastname: Remião
authors.affiliation: CIQ/Department of Chemistry and Biochemistry, Faculty of Sciences, University of Porto , Rua do Campo Alegre s/n, 4169-007 Porto, Portugal.
authors.forename: Fernanda
authors.initials: F
authors.lastname: Borges
mesh_terms: D000818:Animals; D001577:Benzophenones / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D001812:Blood-Brain Barrier / Q000187:drug effects* / Q000378:metabolism; D002394:Catechol O-Methyltransferase / Q000378:metabolism*; D065098:Catechol O-Methyltransferase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D002396:Catechols / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D022781:Hepatocytes / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D008958:Models, Molecular; D015394:Molecular Structure; D009570:Nitriles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D009596:Nitrophenols / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D013329:Structure-Activity Relationship; D000077867:Tolcapone
chemical_list: D001577:Benzophenones; D065098:Catechol O-Methyltransferase Inhibitors; D002396:Catechols; D009570:Nitriles; D009596:Nitrophenols; C071192:entacapone; D000077867:Tolcapone; D002394:Catechol O-Methyltransferase