A ROCK2 inhibitor
Chroman 1 is a highly potent ROCK-II inhibitor. ROCK is a member of the AGC kinase family of serine/threonine kinases that is comprised of two highly homologous isoforms, which are ROCK-I and ROCK-II.. As one of the downstream effectors of RhoA, ROCK regulates stress fiber formation and actin cytoskeletal organization via phosphorylation of myosin light chain. Currently, there is plenty of interest in the inhibition of Rho kinase (ROCK) to treat various diseases.
In vitro: Chroman 1 was found to be a sub-nanomolar ROCK-II inhibitor with excellent to moderate selectivity over related kinases studied as a preliminary assessment, such as AKT1, protein kinase A (PKA), and the highly homologous Cdc42-binding kinase. In addition, Chroman 1 also showed good in-vitro activity in the functional cell-based myosin light chain bis-phosphorylation assay [1].
In vivo: Pharmacokinetic evaluation in rats showed that Chroman 1 had moderately improved oral bioavailability (27–35%) relative to its lead compounds, which were benzodioxane and chroman. In addition, Chroman 1 also displayed an unique intriguing pharmacokinetic profile, which was with high systemic exposure through oral delivery [1].
Clinical trial: So far, there is no clinical study reported.
参考文献:
[1] Chen YT,Bannister TD,Weiser A,Griffin E,Lin L,Ruiz C,Cameron MD,Schürer S,Duckett D,Schrter T,LoGrasso P,Feng Y.? Chroman-3-amides as potent Rho kinase inhibitors. Bioorg Med Chem Lett.2008 Dec 15;18(24):6406-9.
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Kinase experiment: |
Assays are performed using the HTRF KinEASE STK S2 kit. A 5 μL mixture of 1 μM STK2 substrate and 20 μM ATP in STK-buffer is added to the wells. Inhibitor (including Chroman 1, 20 nL) at various concentrations is then dispensed. Reaction is started by addition of 0.5 nM ROCK-II in STK-buffer (5 μL). After 4 h at room temperture (rt), the reaction is stopped by addition of 10 μL mixture of 1× STK antibody-Cryptate in detection buffer and 62.5 nM Sa-XL in detection buffer. After 1 h at rt, the plates are read on the Viewlux in HTRF mode[1]. |
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参考文献: [1]. Yen Ting Chen, et al. Asymmetric synthesis of potent chroman-based Rho kinase (ROCK-II) inhibitors. Med.Chem.Commun., 2011, 2, 73-75. |
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