title: Design and synthesis of Rho kinase inhibitors (II).
abstract: In a previous study, we identified several structurally unrelated scaffolds of the Rho kinase inhibitor using pharmacophore information obtained from the results of a high-throughput screening and structural information from a homology model of Rho kinase. 1H-Indazole is one of the candidate scaffolds on which a new series of potent Rho kinase inhibitors could be developed. In this study, the detailed structure-activity relationship of 1H-indazole analogues was studied. During this study, we found that the cell-free enzyme inhibitory potential of Rho kinase inhibitors having the 1H-indazole scaffold did not necessarily correlate with their inhibitory potential toward the chemotaxis of cultured cells. The choice of the linker substructure was shown to be an important factor for the 1H-indazole analogues to inhibit the chemotaxis of cells. Optimization of the 1H-indazole inhibitors with respect to the in vitro inhibition of monocyte chemotaxis induced by MCP-1 was carried out. The inhibitory potential was improved both in the cell-free enzyme assay and in the chemotaxis assay.
authors.affiliation: Pharmaceutical Research Laboratories, Kirin Brewery Co. Ltd, 3 Miyahara-cho, Takasaki-shi, Gunma 370-1295, Japan.
authors.forename: Masayuki
authors.initials: M
authors.lastname: Iwakubo
authors.forename: Atsuya
authors.initials: A
authors.lastname: Takami
authors.forename: Yuji
authors.initials: Y
authors.lastname: Okada
authors.forename: Takehisa
authors.initials: T
authors.lastname: Kawata
authors.forename: Yoshimichi
authors.initials: Y
authors.lastname: Tagami
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Ohashi
authors.forename: Motoko
authors.initials: M
authors.lastname: Sato
authors.forename: Terumi
authors.initials: T
authors.lastname: Sugiyama
authors.forename: Kayoko
authors.initials: K
authors.lastname: Fukushima
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Iijima
mesh_terms: D001665:Binding Sites; D045744:Cell Line, Tumor; D002633:Chemotaxis / Q000187:drug effects; D015195:Drug Design; D004353:Drug Evaluation, Preclinical; D006801:Humans; D007191:Indazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D047908:Intracellular Signaling Peptides and Proteins / Q000037:antagonists & inhibitors*; D008024:Ligands; D008958:Models, Molecular; D015394:Molecular Structure; D009000:Monocytes / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D054460:rho-Associated Kinases
chemical_list: D007191:Indazoles; D047908:Intracellular Signaling Peptides and Proteins; D008024:Ligands; D047428:Protein Kinase Inhibitors; D017346:Protein Serine-Threonine Kinases; D054460:rho-Associated Kinases