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

N-(1-benzyl-3-pyrrolidyl)-N-(5-isoquinolyl)amine analogues were optimized efficacy based on the in vitro Rho kinase inhibition, the cell-based chemotaxis inhibition, and the ex vivo test.Figure optionsDownload as PowerPoint slide