Design and synthesis of rho kinase inhibitors (III).

Article Details


Iwakubo M, Takami A, Okada Y, Kawata T, Tagami Y, Sato M, Sugiyama T, Fukushima K, Taya S, Amano M, Kaibuchi K, Iijima H

Design and synthesis of rho kinase inhibitors (III).

Bioorg Med Chem. 2007 Jan 15;15(2):1022-33. Epub 2006 Oct 18.

PubMed ID
17084087 [ View in PubMed

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.

DrugBank Data that Cites this Article

Binding Properties
DrugTargetPropertyMeasurementpHTemperature (°C)
FasudilRho-associated protein kinase 1IC 50 (nM)180N/AN/ADetails