Design and synthesis of rho kinase inhibitors (III).
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.
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
Sato
Motoko
M
Sugiyama
Terumi
T
Fukushima
Kayoko
K
Taya
Shinichiro
S
Amano
Mutsuki
M
Kaibuchi
Kozo
K
Iijima
Hiroshi
H
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
D004791:Enzyme Inhibitors; D047908:Intracellular Signaling Peptides and Proteins; D007546:Isoquinolines; D008024:Ligands; D017346:Protein Serine-Threonine Kinases; D054460:rho-Associated Kinases