title: Design and synthesis of rho kinase inhibitors (III).
abstract: The structure-activity relationship of Rho kinase inhibitors bearing an isoquinoline scaffold was studied. N-(1-Benzyl-3-pyrrolidyl)-N-(5-isoquinolyl)amine analogues were optimized with respect to their inhibitory potencies for the enzyme and for chemotaxis. The potent analogues were further evaluated by an ex vivo test in which the selected compounds were orally administered to rats, and the Rho kinase inhibitory potency observed in the rat serum was evaluated 3h after the administration. Compound 23g showed a high level of Rho kinase inhibitory activity in the rat serum and was stable in an in vitro metabolic test using a microsomal cytochrome preparation. The (R)-isomer of 23g displayed a higher level of inhibitory potency than the (S)-isomer in a cell-free kinase assay and in the cell migration assay (IC(50)(ENZ)=25 nM and IC(50)(MCP)=1 microM). The (R)-isomer successfully inhibited the phosphorylation of MBS (myosin-binding subunit) in cells.
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: 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: Shinichiro
authors.initials: S
authors.lastname: Taya
authors.forename: Mutsuki
authors.initials: M
authors.lastname: Amano
authors.forename: Kozo
authors.initials: K
authors.lastname: Kaibuchi
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Iijima
mesh_terms: D000478:Alkylation; D000818:Animals; D002460:Cell Line; D002634:Chemotaxis, Leukocyte / Q000187:drug effects; D004285:Dogs; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology*; D066298:In Vitro Techniques; D047908:Intracellular Signaling Peptides and Proteins / Q000037:antagonists & inhibitors*; D007546:Isoquinolines / Q000138:chemical synthesis* / Q000494:pharmacology*; D007668:Kidney / Q000187:drug effects / Q000201:enzymology; D008024:Ligands; D009682:Magnetic Resonance Spectroscopy; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology; D008958:Models, Molecular; D010084:Oxidation-Reduction; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D051381:Rats; D017207:Rats, Sprague-Dawley; D021241:Spectrometry, Mass, Electrospray Ionization; D013329:Structure-Activity Relationship; D054460:rho-Associated Kinases
chemical_list: D004791:Enzyme Inhibitors; D047908:Intracellular Signaling Peptides and Proteins; D007546:Isoquinolines; D008024:Ligands; D017346:Protein Serine-Threonine Kinases; D054460:rho-Associated Kinases