title: Rho-kinase inhibitors: pharmacomodulations on the lead compound Y-32885.
abstract: 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.
authors.affiliation: Laboratoire de Chimie Thérapeutique, Faculté des Sciences Pharmaceutiques et Biologiques, BP 83, 59006 Lille Cedex, France.
authors.forename: Cédric
authors.initials: C
authors.lastname: Logé
authors.forename: Valérie
authors.initials: V
authors.lastname: Wallez
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Scalbert
authors.forename: Christelle
authors.initials: C
authors.lastname: Cario-Tourmaniantz
authors.forename: Gervaise
authors.initials: G
authors.lastname: Loirand
authors.forename: Pierre
authors.initials: P
authors.lastname: Pacaud
authors.forename: Daniel
authors.initials: D
authors.lastname: Lesieur
mesh_terms: D000199:Actins / Q000187:drug effects; D000818:Animals; D001011:Aorta / Q000166:cytology; D001549:Benzamides / Q000737:chemistry* / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D016244:Guanosine 5'-O-(3-Thiotriphosphate) / Q000494:pharmacology; D006168:Guinea Pigs; D066298:In Vitro Techniques; D020128:Inhibitory Concentration 50; D047908:Intracellular Signaling Peptides and Proteins; D009119:Muscle Contraction / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000187:drug effects; D010539:Permeability; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000737:chemistry; D011725:Pyridines / Q000737:chemistry* / Q000494:pharmacology*; D051381:Rats; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D054460:rho-Associated Kinases
chemical_list: D000199:Actins; D001549:Benzamides; D004791:Enzyme Inhibitors; D047908:Intracellular Signaling Peptides and Proteins; D011725:Pyridines; C460080:Y 32885; D016244:Guanosine 5'-O-(3-Thiotriphosphate); D017346:Protein Serine-Threonine Kinases; D054460:rho-Associated Kinases