Development of new Rac1 inhibitors as potential pharmacological agents for the treatment of atherosclerotic disease

Background and Purpose - Rac1 protein is implicated in several events of atherosclerotic plaque development and represents a new potential pharmacological target for cardiovascular diseases. The aim of this study was to discover new classes of Rac1 inhibitors, in order to obtain a specific inhibitory action on a biological function of Rac1 we screen for the identification of small molecules capable to interfere with mechanism of activation of this protein. Methods and Results A total of 59 commercially available N-(sulphamoylaryl) arylamides with variations in 2 specific regionswere selected and acquired for biochemical testing,.From this compounds 6 showed a potent inhibitory action on Rac1 activity in human smooth muscle cells (SMCs) as determined by G-LISA assay. These compounds show to be more effective than the reference compound NSC23766 in reducing the intracellular levels of Rac1-GTP. The most promising compound Rac6 shows a selective inhibitory action on Rac1 (IC50= 8.7M) without any significant effect on RhoA activity. This pharmacological inhibition determined a profound effect on cytoskeleton organization of human cultured SMCs and an inhibitory effect on cell adhesion (IC50= 7.9 M) and migration. Conclusions -We have identified new selective Rac1 inhibitor with potential pharmacological activities on SMC accumulation in atherosclerotic lesions. At the same time we started to tests the compound Rac6 in an in vivo model of atherosclerosis by performing preliminary pharmacokinetic studies. These analysis may help to better understand both the role of Rac1 in atherogenesis and to identify a new potential pharmacological intervention for this disease.