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

• Type: Article in International Scientific Journal
• Date: 2016

Authors

Silva, T (Author) Other; Mohamed, T (Author) Other; Shakeri, A (Author) Other; Rao, PPN (Author) Other; Martinez Gonzalez, L (Author) Other; Perez, DI (Author) Other; Martinez, A (Author) Other; Valente, MJ (Author) Other; Garrido, J (Author) Other; Uriarte, E (Author) Other; Maria Paula Serrão (Author) FMUP; Soares da Silva, P (Author) Other; Fernando Remiao (Author) FFUP; Fernanda Borges (Author) FCUP

Journal

Title: Journal of Medicinal Chemistry

Vol. 59

Pages: 7584-7597

ISSN: 0022-2623

Publisher: American Chemical Society

Indexing

ISI Web of Knowledge - 32 Citations

Scopus - 35 Citations

Other information

Authenticus ID: P-00K-T5Q

DOI: 10.1021/acs.jmedchem.6b00666

Abstract (EN): 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 mu M 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.

Language: English

Type (Professor's evaluation): Scientific

No. of pages: 14