Synthesis, biological evaluation, and molecular modeling studies of a novel peripherally selective inhibitor of catechol-O-methyltransferase

• Type: Article in International Scientific Journal
• Date: 2004

Authors

learmonth, da (Author) Other; palma, pn (Author) Other; vieira-coelho, ma (Author) FMUP; soares-da-silva, p (Author) FMUP

Journal

Title: Journal of Medicinal Chemistry

Vol. 47

Pages: 6207-6217

ISSN: 0022-2623

Publisher: American Chemical Society

Indexing

ISI Web of Knowledge - 33 Citations

Scopus - 35 Citations

Scientific classification

FOS: Medical and Health sciences > Basic medicine

Other information

Authenticus ID: P-000-7CA

DOI: 10.1021/jm040848o

Abstract (EN): A novel series of potent, peripherally selective, and long-acting inhibitors of catechol-O-methyltransferase (COMT) has been synthesized. The introduction and nature of heteroatomcontaining substituents to the side-chain of the nitrocatechol pharmacophore was found to have a profound effect on both peripheral selectivity and duration of COMT inhibition in the mouse. This approach led to the discovery of 1-(3,4-dihydroxy-5-nitrophenyl)-3-[4-[3-(trifluoromethyl)phenyl]-1-piperaziny1]-1-propanone hydrochloride 35 (BIA 3-335), which was found to possess a superior inhibitory profile in vivo over both the nonselective inhibitor tolcapone 1 and the peripherally selective but short-acting entacapone 2. In this model, 35 retained 75% inhibition of peripheral COMT at 6 h after oral administration, yet significantly, only a minor reduction of central (cerebral) COMT activity was observed. Molecular modeling techniques were applied to review the analysis of the ternary enzyme-inhibitor complex previously determined by X-ray crystallography and to provide a deeper understanding of the structure-activity relationships within this novel series. Furthermore, a computational approach was applied in an effort to elucidate the particular structural factors relevant to the poor blood-brain permeability of 35. In conclusion, the improved biological properties herein reported reveal 35 as a candidate for clinical studies as an adjunct to L-DOPA therapy for Parkinson's disease.

Language: English

Type (Professor's evaluation): Scientific

No. of pages: 11