Synthesis of 1-(3,4-dihydroxy-5-nitrophenyl)-2-phenyl-ethanone and derivatives as potent and long-acting peripheral inhibitors of catechol-O-methyltransferase

• Type: Article in International Scientific Journal
• Date: 2002

Authors

learmonth, da (Author) Other; vieira-coelho, ma (Author) FMUP; benes, j (Author) Other; alves, pc (Author) Other; borges, n (Author) FCNAUP; freitas, ap (Author) Other; soares-da-silva, p (Author) FMUP

Journal

Title: Journal of Medicinal Chemistry

Vol. 45

Pages: 685-695

ISSN: 0022-2623

Publisher: American Chemical Society

Indexing

ISI Web of Knowledge - 47 Citations

Scopus - 55 Citations

Scientific classification

FOS: Medical and Health sciences > Basic medicine

Other information

Authenticus ID: P-000-QJB

DOI: 10.1021/jm0109964

Abstract (EN): A homologous series of novel nitro-catechol structures (7a-7e) were synthesized and tested as inhibitors of the enzyme catechol-O-methyltransferase (COMT). Increasing chain length was found to have significant impact on both brain penetration and duration of COMT inhibition in the rat. Of this series, compound 7b (1-(3,4-dihydroxy-5-nitrophenyl)-2-phenyl-ethanone) was found to exhibit the most potent and selective inhibition of peripheral COMT, with an inhibition profile more similar to entacapone 2 than tolcapone 1 (an equipotent peripheral and central inhibitor) but with much improved duration of action (7b, 70% inhibition and 2, 25% inhibition at 9 h after administration). The effects of structural modifications to 7b on COMT inhibitory profile were investigated, and it is concluded that the carbonyl group and preferably unsubstituted aromatic ring are essential features to maintain prolonged peripheral COMT inhibition. The introduction of the alpha-methylene group, the major structural difference between 7b and 1, would appear responsible for the observed enhancement in selectivity of peripheral COMT inhibition of 7b, which has more limited access to the brain than 1.

Language: English

Type (Professor's evaluation): Scientific

No. of pages: 11