Design and synthesis of rho kinase inhibitors (III)

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.

Elaborate ligand-based modeling reveal new submicromolar Rho kinase inhibitors

“…The structures of ROCK II inhibitors (1-138, Tables A1 and A2 under supplementary material) were collected from recently published literature [7][8][9]. Despite that the collected inhibitors were gathered from three separate articles, they were bioassayed employing the same bioassay methodology.…”

“…The fact that we have an informative list of 138 ROCKII inhibitors of evenly spread bioactivities over more than 3.5 orders of magnitude, prompted us to employ CATALYST-HYPOGEN to identify possible pharmacophoric binding modes assumed by ROCKII inhibitors [7][8][9].…”

“…The main focus of recent efforts towards the development of new ROCK II inhibitors concentrate on structurebased ligand design [7][8][9][10]. To date, several human ROCK II complexes have been resolved by X-ray crystallography and solution NMR, e.g., PDB codes: 2H9V, 2ROW, 2ROV, 2F2U [11][12][13][14].…”

“…We employed the CATALYST-HYPOGEN module of the software package Discovery Studio [35] to construct plausible binding hypotheses for a diverse list of ROCKII inhibitors [7][8][9]. Subsequently, genetic function algorithm (GFA) and multiple linear regression (MLR) analyses were employed to search for an optimal QSAR that combine high-quality binding pharmacophores with other molecular descriptors capable of explaining bioactivity variation across a collection of diverse ROCK II inhibitors.…”

Design, Synthesis, and Biological Evaluations of Several Fasudil Analogues

“…Fasudil effectively reduces the onset and clinical symptoms of EAE and also decreases the peripheral inflammatory response and improves the CNS microenvironment. Over the past two decades, Rho kinase inhibitors have been studied intensively . Chen et al .…”