A11, a novel diaryl acylhydrazone derivative, exerts neuroprotection against ischemic injury in vitro and in vivo.

There is an urgent need to develop effective therapies for ischemic stroke, but the complicated pathological processes after ischemia make doing so difficult. In the current study, we identified a novel diaryl acylhydrazone derivative, A11, which has multiple neuroprotective properties in ischemic stroke models. First, A11 was demonstrated to induce neuroprotection against ischemic injury in a dose-dependent manner (from 0.3 to 3 µM) in three in vitro experimental ischemic stroke models: oxygen glucose deprivation (OGD), hydrogen peroxide, and glutamate-stimulated neuronal cell injury models. Moreover, A11 was able to potently alleviate three critical pathological changes, apoptosis, oxidative stress, and mitochondrial dysfunction, following ischemic insult in neuronal cells. Further analysis revealed that A11 upregulated the phosphorylation levels of protein kinase B (AKT) and extracellular signal-regulated kinase (ERK) in OGD-exposed neuronal cells, suggesting joint activation of the phosphoinositide 3-kinase (PI3K)/AKT and mitogen-activated protein kinase (MEK)/ERK pathways. In rats with middle cerebral artery occlusion, single-dose administration of A11 (3 mg/kg per day, i.v.) at the onset of reperfusion significantly reduced the infarct volumes and ameliorated neurological deficits. Our study, for the first time, reports the anti-ischemic effect of diaryl acylhydrazone chemical entities, especially A11, which acts on multiple ischemia-associated pathological processes. Our results may provide new clues for the development of an effective therapeutic agent for ischemic stroke.

A novel series of 4-methyl substituted pyrazole derivatives as potent glucagon receptor antagonists: Design, synthesis and evaluation of biological activities.

A novel series of 4-methyl substituted pyrazole derivatives were designed, synthesized and biologically evaluated as potent glucagon receptor (GCGR) antagonists. In this study, compounds 9q, 9r, 19d and 19e showed high GCGR binding (IC50 = 0.09 µM, 0.06 µM, 0.07 µM and 0.08 µM, respectively) and cyclic-adenosine monophosphate (cAMP) activities (IC50 = 0.22 µM, 0.26 µM, 0.44 µM and 0.46 µM, respectively) in cell-based assays. Most importantly, the docking experiment demonstrated that compound 9r formed extensive hydrophobic interactions with the receptor binding pocket, making it justifiable to further investigate the potential of becoming a GCGR antagonist.

Discovery of thiophene-containing biaryl amide derivatives as novel glucagon receptor antagonists.

A novel series of thiophene-containing biaryl amide glucagon receptor (GCGR) antagonists were designed and synthesized. Two compounds of this series, 14f and 14h, exhibited good GCGR binding (IC50  = 6.1 and 4.4 µm, respectively) and cAMP functional activities (IC50  = 4.4 and 14.4 µm, respectively). The possible binding modes of compounds 14f and 14h with GCGR were explored by molecular simulation.