Design and synthesis of rho kinase inhibitors (III)

Masayuki Iwakubo, Atsuya Takami, Yuji Okada, Takehisa Kawata, Yoshimichi Tagami, Motoko Sato, Terumi Sugiyama, Kayoko Fukushima, Shinichiro Taya, Mutsuki Amano, Kozo Kaibuchi, Hiroshi Iijima

Research output: Contribution to journalArticlepeer-review

46 Citations (Scopus)


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 3 h 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 (IC50ENZ = 25 nM and IC50MCP = 1 μ M). The (R)-isomer successfully inhibited the phosphorylation of MBS (myosin-binding subunit) in cells.

Original languageEnglish
Pages (from-to)1022-1033
Number of pages12
JournalBioorganic and Medicinal Chemistry
Issue number2
Publication statusPublished - 15-01-2007
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmaceutical Science
  • Drug Discovery
  • Clinical Biochemistry
  • Organic Chemistry


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