Experimental and clinical observations have documented the role of the small GTPase Rac1 protein in cardiovascular diseases opening to a new potential pharmacological intervention. In this study a new class of selective Rac inhibitors with the 3-aryl-1H-pyrazole-5-carboxamide nucleus was characterized. Starting from our previous identification of Rac inhibitors [1], through a computational approach, 57 chemical entities were identified and their Rac inhibitory efficacy evaluated by G-LISA assay. 23 compounds were found to reduce Rac-GTP levels in cultured cells by more than 24.8%. Compounds 4, 5, 6, 11 and 21 resulted the most potent without interfering with RhoA protein activity, with compound 11 that was less Rac-selective. The IC50s for Rac inhibition of compounds 3, 4, 5 and 21 were between 4.4 and 29.1 μM. The treatment with compound 4 strongly reduced the Rac1-GTP levels induced by SMCs expressing Tiam1, TrioN, or Vav2. Compound 4 inhibited SMC migration in response to PDGF-BB in a concentration dependent manner with an IC50 value of 5.8 µM. The incubation of human monocytic cell line THP-1 with compound 4 (10 µM) completely abrogated their adhesion to cultured human umbilical endothelial cells (HUVEC) indicating a potent anti-inflammatory activity. A preliminary pharmacodynamic study in C57BL/6 mice was performed by administering compound 4 at 50 and 100 mg/kg i.p. At these doses, a 35% (50 mg/kg) and 70% (100 mg/kg) reduction of Rac1-GTP levels were observed in heart homogenates. In conclusion, in the present study we identified a new selective Rac inhibitor capable to interfere with SMC migration and monocyte-endothelial cell adhesion, two pivotal features of atherogenesis. Further in vivo studies will be performed to study the effect of Rac inhibition on cardiac hypertrophy. EU grant # 018671 CARDIOWORKBENCH FIRB – Programma “Futuro in Ricerca”” grant # RBFR087YAY [1] Ferri N, et al. J Med Chem 2009, 52; 4087-4090
Development of new Rac1 inhibitors as potential pharmacological agents for the treatment of atherosclerosis / S.K. Bernini, A. Contini, A. Corsini, N. Ferri. ((Intervento presentato al 81. convegno European Atherosclerosis Society Congress tenutosi a Lione nel 2013.
Development of new Rac1 inhibitors as potential pharmacological agents for the treatment of atherosclerosis
A. Contini;A. Corsini;N. Ferri
2013
Abstract
Experimental and clinical observations have documented the role of the small GTPase Rac1 protein in cardiovascular diseases opening to a new potential pharmacological intervention. In this study a new class of selective Rac inhibitors with the 3-aryl-1H-pyrazole-5-carboxamide nucleus was characterized. Starting from our previous identification of Rac inhibitors [1], through a computational approach, 57 chemical entities were identified and their Rac inhibitory efficacy evaluated by G-LISA assay. 23 compounds were found to reduce Rac-GTP levels in cultured cells by more than 24.8%. Compounds 4, 5, 6, 11 and 21 resulted the most potent without interfering with RhoA protein activity, with compound 11 that was less Rac-selective. The IC50s for Rac inhibition of compounds 3, 4, 5 and 21 were between 4.4 and 29.1 μM. The treatment with compound 4 strongly reduced the Rac1-GTP levels induced by SMCs expressing Tiam1, TrioN, or Vav2. Compound 4 inhibited SMC migration in response to PDGF-BB in a concentration dependent manner with an IC50 value of 5.8 µM. The incubation of human monocytic cell line THP-1 with compound 4 (10 µM) completely abrogated their adhesion to cultured human umbilical endothelial cells (HUVEC) indicating a potent anti-inflammatory activity. A preliminary pharmacodynamic study in C57BL/6 mice was performed by administering compound 4 at 50 and 100 mg/kg i.p. At these doses, a 35% (50 mg/kg) and 70% (100 mg/kg) reduction of Rac1-GTP levels were observed in heart homogenates. In conclusion, in the present study we identified a new selective Rac inhibitor capable to interfere with SMC migration and monocyte-endothelial cell adhesion, two pivotal features of atherogenesis. Further in vivo studies will be performed to study the effect of Rac inhibition on cardiac hypertrophy. EU grant # 018671 CARDIOWORKBENCH FIRB – Programma “Futuro in Ricerca”” grant # RBFR087YAY [1] Ferri N, et al. J Med Chem 2009, 52; 4087-4090
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