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Updated: Jul 19, 2026

Identification of Mediators of T-cell Receptor Signaling via the Screening of Chemical Inhibitor Libraries
Published on: January 22, 2019
Design and synthesis of rho kinase inhibitors (III)
Masayuki Iwakubo1, Atsuya Takami, Yuji Okada
1Pharmaceutical Research Laboratories, Kirin Brewery Co. Ltd., 3 Miyahara-cho, Takasaki-shi, Gunma 370-1295, Japan.
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.
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