Design and synthesis of Rho kinase inhibitors (I).
Several structurally unrelated scaffolds of the Rho kinase inhibitor were designed using pharmacophore information obtained from the results of a high-throughput screening and structural information from a homology model of Rho kinase. A docking simulation using the ligand-binding pocket of the Rho kinase model helped to comprehensively understand and to predict the structure-activity relationship of the inhibitors. This understanding was useful for developing new Rho kinase inhibitors of higher potency and selectivity. We identified several potent platforms for developing the Rho kinase inhibitors, namely, pyridine, 1H-indazole, isoquinoline, and phthalimide.
Takami
Atsuya
A
Pharmaceutical Research Laboratories, Kirin Brewery Co. Ltd, 3 Miyhara-cho, Takasaki-shi, Gunma 370-1295, Japan.
Iwakubo
Masayuki
M
Okada
Yuji
Y
Kawata
Takehisa
T
Odai
Hideharu
H
Takahashi
Nobuaki
N
Shindo
Kazutoshi
K
Kimura
Kaname
K
Tagami
Yoshimichi
Y
Miyake
Mika
M
Fukushima
Kayoko
K
Inagaki
Masaki
M
Amano
Mutsuki
M
Kaibuchi
Kozo
K
Iijima
Hiroshi
H
D000595:Amino Acid Sequence; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry* / Q000494:pharmacology; D047908:Intracellular Signaling Peptides and Proteins; D008024:Ligands; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D008969:Molecular Sequence Data; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors; D017386:Sequence Homology, Amino Acid; D021241:Spectrometry, Mass, Electrospray Ionization; D054460:rho-Associated Kinases
D004791:Enzyme Inhibitors; D047908:Intracellular Signaling Peptides and Proteins; D008024:Ligands; D017346:Protein Serine-Threonine Kinases; D054460:rho-Associated Kinases