title: Synthesis and pharmacological study of Rho-kinase inhibitors: pharmacomodulations on the lead compound Fasudil.
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.
authors.affiliation: Faculté des Sciences Pharmaceutiques et Biologiques, BP 83, 59006 Lille Cedex, France. cloge@phare.univ-lille2.fr
authors.forename: Cédric
authors.initials: C
authors.lastname: Logé
authors.forename: Xavier
authors.initials: X
authors.lastname: Siomboing
authors.forename: Valérie
authors.initials: V
authors.lastname: Wallez
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Scalbert
authors.forename: Caroline
authors.initials: C
authors.lastname: Bennejean
authors.forename: Christelle
authors.initials: C
authors.lastname: Cario-Tourmaniantz
authors.forename: Gervaise
authors.initials: G
authors.lastname: Loirand
authors.forename: Bernard
authors.initials: B
authors.lastname: Gressier
authors.forename: Pierre
authors.initials: P
authors.lastname: Pacaud
authors.forename: Michel
authors.initials: M
authors.lastname: Luyckx
mesh_terms: D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D002470:Cell Survival / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D066298:In Vitro Techniques; D047908:Intracellular Signaling Peptides and Proteins; D015394:Molecular Structure; D009504:Neutrophils / Q000187:drug effects / Q000201:enzymology*; D011493:Protein Kinase C / Q000037:antagonists & inhibitors; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship; D054460:rho-Associated Kinases
chemical_list: D004791:Enzyme Inhibitors; D047908:Intracellular Signaling Peptides and Proteins; D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; D017346:Protein Serine-Threonine Kinases; D054460:rho-Associated Kinases; D011493:Protein Kinase C; C049347:fasudil