Synthesis and biological evaluation of a novel series of "ortho-nitrated" inhibitors of catechol-O-methyltransferase.
J Med Chem
; 48(25): 8070-8, 2005 Dec 15.
Article
en En
| MEDLINE
| ID: mdl-16335931
ABSTRACT
Novel regioisomeric "ortho-nitrated" catechols related to the catechol-O-methyltransferase (COMT) inhibitors BIA 3-202 3 and BIA 3-335 4 were synthesized and biologically evaluated. Changing the position of the nitro group from the "classical" meta- to the ortho-position relative to the side-chain substituent of the nitrocatechol pharmacophore exerted profound effects on selectivity and duration of COMT inhibition. Alkylaryl compounds 7a-d possessed shorter duration of action than their regioisomers, but 7b displayed reversed selectivity over 3 at 3 and 6 h, exhibiting preferential central inhibition. In the amino-substituted series, ortho-nitrated regioisomer 14k was less peripherally selective than 4 and short-acting, whereas decahydroquinoline 14g displayed an unprecedented combination of long-acting and selective peripheral inhibition. 7b could provide a useful tool to probe the pharmacological utility of short-acting, centrally selective COMT inhibitors in the treatment of depression in Parkinsonian patients, and 14g represents a promising candidate for clinical evaluation as an adjunct to L-Dopa therapy.
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Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Catecoles
/
Inhibidores de Catecol O-Metiltransferasa
/
Nitrocompuestos
Límite:
Animals
/
Humans
Idioma:
En
Revista:
J Med Chem
Asunto de la revista:
QUIMICA
Año:
2005
Tipo del documento:
Article
País de afiliación:
Portugal