Synthesis and pharmacological study of Rho-kinase inhibitors: pharmacomodulations on the lead compound Fasudil.
J Enzyme Inhib Med Chem
; 18(2): 127-38, 2003 Apr.
Article
em En
| MEDLINE
| ID: mdl-12943196
ABSTRACT
With a view to specifying structure-activity relationships we have synthesised a new series of analogues of the Rho-kinase inhibitor 1-(5-isoquinolinesulfonyl)-homopiperazine (Fasudil). The structural modifications concerned the isoquinolinyl heterocycle and the sulfonyl group which are the two main features of this lead compound. These analogues were evaluated on the actin cytoskeleton and on the enzymatic activity of Rho-kinase. Most of the chemical modifications result in a loss of activity showing that interactions of Fasudil with the catalytic domain of Rho-kinase seem to be particularly definite and sensitive to structural variations. The presence of an isoquinolinyl nitrogen and a basic amino group separated by a spacer bearing a sulfonamide function are of utmost importance. Only the tetra-hydroisoquinoline analogue 3 shows the same activity as Fasudil. Moreover, this compound is unable to inhibit PKC biological activity contrary to Fasudil. The loss of the aromatic property could increase the selectivity level in favour of compound 3.
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Base de dados:
MEDLINE
Assunto principal:
Proteínas Serina-Treonina Quinases
/
1-(5-Isoquinolinasulfonil)-2-Metilpiperazina
/
Inibidores Enzimáticos
/
Neutrófilos
Limite:
Humans
Idioma:
En
Revista:
J Enzyme Inhib Med Chem
Assunto da revista:
BIOQUIMICA
/
QUIMICA
Ano de publicação:
2003
Tipo de documento:
Article
País de afiliação:
França