Design and synthesis of Rho kinase inhibitors (II).
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.
Iwakubo
Masayuki
M
Pharmaceutical Research Laboratories, Kirin Brewery Co. Ltd, 3 Miyahara-cho, Takasaki-shi, Gunma 370-1295, Japan.
Takami
Atsuya
A
Okada
Yuji
Y
Kawata
Takehisa
T
Tagami
Yoshimichi
Y
Ohashi
Hiroshi
H
Sato
Motoko
M
Sugiyama
Terumi
T
Fukushima
Kayoko
K
Iijima
Hiroshi
H
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
D007191:Indazoles; D047908:Intracellular Signaling Peptides and Proteins; D008024:Ligands; D047428:Protein Kinase Inhibitors; D017346:Protein Serine-Threonine Kinases; D054460:rho-Associated Kinases