Rho-kinase inhibitors: pharmacomodulations on the lead compound Y-32885.

In order to specify structure-activity relationships we have synthesized new series of analogues of the Rho-kinase inhibitor (R)-(+)-N-(4-pyridyl)-4-(1-aminoethyl)benzamide (Y-32885). The structural modifications concerned the 1-aminoethyl, the pyridyl and the amide groups which are the main features of this lead compound. Our analogue derivatives were evaluated on GTPgammaS-induced contraction in permeabilized smooth-muscle and on the actin cytoskeleton. All the modifications result in a diminution or a loss of activity showing that interactions of Y-32885 with the catalytic domain of Rho-kinase seem to be particularly definite and sensitive to structural variations. The presence of a pyridine moiety and a basic amine group separated by a spacer bearing an amide function are of utmost importance.