SSR149744C (2-butyl-3-{4-[3-(dibutylamino)propyl]benzoyl}-1-benzofuran-5-carboxylate isopropyl fumarate) is a new noniodinated benzofuran derivative structurally related to amiodarone and dronedarone that is currently undergoing clinical trials as an antiarrhythmic agent. As SSR149744C exhibits electrophysiological and hemodynamic properties of class I, II, III, and IV antiarrhythmic agents, the aim of this study was to evaluate its acute intravenous (IV) or oral (PO) antiarrhythmic activities in in vitro and in vivo animal models of atrial and ventricular arrhythmias. In vagally induced atrial fibrillation (AF) in anesthetized dogs, SSR149744C (3 and 10 mg/kg IV) terminated AF in all 7 dogs and prevented reinduction in 4 out of 7 dogs; effective refractory periods of right atrium were dose-dependently and frequency-independently lengthened. In low-K+ medium-induced AF models, SSR149744C (0.1 to 1 microM) prevented AF in isolated guinea pig hearts in a concentration-dependent manner. At the ventricular level, SSR149744C (0.1 to 10 mg/kg IV and 3 to 90 mg/kg PO) prevented reperfusion-induced arrhythmias in anesthetized rats with a dose-effect relationship, and, at doses of 30 to 90 mg/kg PO, it reduced early (0-24 hours) mortality following permanent left coronary artery ligature in conscious rats. The present results show that SSR149744C is an effective antiarrhythmic agent in atrial fibrillation and in ventricular arrhythmias. Like amiodarone and dronedarone, its efficiency in these animal models of arrhythmias is likely be related to its multifactorial mechanism of action.

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Age-related hearing loss (ARHL) is the most common sensory disorder in the elderly population. SAMP8 mouse model presents accelerated senescence and has been identified as a model of gerontological research. SAMP8 displays a progressive age-related decline in brain function associated with a progressive hearing loss mimicking human aging memory deficits and ARHL. The molecular mechanisms associated with SAMP8 senescence process involve oxidative stress leading to chronic inflammation and apoptosis. Here, we studied the effect of N-acetylcysteine (NAC), an antioxidant, on SAMP8 hearing loss and memory to determine the potential interest of this model in the study of new antioxidant therapies. We observed a strong decrease of auditory brainstem response thresholds from 45 to 75 days of age and an increase of distortion product amplitudes from 60 to 75 days in NAC treated group compared to vehicle. Moreover, NAC treated group presented also an increase of memory performance at 60 and 105 days of age. These results confirm that NAC delays the senescence process by slowing the age-related hearing loss, protecting the cochlear hair cells and improving memory, suggesting that antioxidants could be a pharmacological target for age-related hearing and memory loss.

SAR103168, a tyrosine kinase inhibitor of the pyrido [2,3-d] pyridimidine subclass, inhibited the kinase activities of the entire Src kinase family, Abl kinase, angiogenic receptor kinases (vascular endothelial growth factor receptor [VEGFR] 1 and 2), Tie2, platelet derived growth factor (PDGF), fibroblast growth factor receptor (FGFR) 1 and 3, and epidermal growth factor receptor (EGFR). SAR103168 was a potent Src inhibitor, with 50% inhibitory concentration (IC50) = 0.65 ± 0.02 nM (at 100 μM ATP), targeting the auto-phosphorylation of the kinase domain (Src(260-535)) and activity of the phosphorylated kinase. Phosphorylation of Src, Lyn and Src downstream signaling pathways (PYK2, P-130CAS, FAK, JNK and MAPK) were inhibited in a dose-dependent manner. SAR103168 inhibited the phosphorylation of STAT5 in KG1 cells and fresh cells from patients with acute myeloid leukemia (AML). SAR103168 inhibited proliferation and induced apoptosis in acute and chronic myeloid leukemic cells at nanomolar IC50. SAR103168 induced anti-proliferation of leukemic progenitors (CFU-L) from 29 patients with AML, and > 85% of AML patient samples were sensitive to SAR103168. These antagonist activities of SAR103168 were independent of FLT3 expression. SAR103168 treatment was effective in 50% of high-risk patient samples carrying chromosome 7 abnormalities or complex rearrangement. SAR103168 administration (intravenous or oral) impaired tumor growth and induced tumor regression in animals bearing human AML leukemic cells, correlating with potent inhibition of Src downstream signaling pathways in AML tumors. SAR103168 showed potent anti-tumor activity in SCID (severe combined immunodeficiency) mice bearing AML (KG1, EOL-1, Kasumi-1, CTV1) and chronic myeloid leukemia (CML) (K562) tumors. The combination of cytarabine and SAR103168 showed synergistic activity in AML and CML tumor models. These results highlight the therapeutic potential of SAR103168 in myeloid leukemias and support the rationale for clinical investigations.

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