Limits...
Discovery of 3-n-butyl-2,3-dihydro-1H-isoindol-1-one as a potential anti-ischemic stroke agent.

Lan Z, Xu X, Xu W, Li J, Liang Z, Zhang X, Lei M, Zhao C - Drug Des Devel Ther (2015)

Bottom Line: This activity is superior to that of 3-n-butylphthalide and comparable with aspirin and edaravone.Meanwhile, 3d not only exhibited a potent activity in scavenging free radicals and improving the survival of HT22 cells against the reactive oxygen species-mediated cytotoxicity in vitro but also significantly attenuated the ischemia/reperfusion-induced oxidative stress in ischemic rat brains.In conclusion, our findings suggest that 3-alkyl-2,3-dihydro-1H-isoindol-1-ones, a novel series of compounds, might be candidate drugs for the treatment of acute ischemic strokes, and 3d may be a promising therapeutic agent for the primary and secondary prevention of ischemic stroke.

View Article: PubMed Central - PubMed

Affiliation: School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, People's Republic of China.

ABSTRACT
To develop novel anti-ischemic stroke agents with better therapeutic efficacy and bioavailability, we designed and synthesized a series of 3-alkyl-2,3-dihydro-1H-isoindol-1-ones compounds (3a-i) derivatives, one of which (3d) exhibited the strongest inhibitory activity for the adenosine diphosphate-induced and arachidonic acid-induced platelet aggregation. This activity is superior to that of 3-n-butylphthalide and comparable with aspirin and edaravone. Meanwhile, 3d not only exhibited a potent activity in scavenging free radicals and improving the survival of HT22 cells against the reactive oxygen species-mediated cytotoxicity in vitro but also significantly attenuated the ischemia/reperfusion-induced oxidative stress in ischemic rat brains. Results from transient middle cerebral artery occlusion and permanent middle cerebral artery occlusion model, indicated that 3d could significantly reduce infarct size, improve neurobehavioral deficits, and prominently decrease attenuation of cerebral damage. Most importantly, 3d possessed a very high absolute bioavailability and was rapidly distributed in brain tissue to keep high plasma drug concentration for the treatment of ischemic strokes. In conclusion, our findings suggest that 3-alkyl-2,3-dihydro-1H-isoindol-1-ones, a novel series of compounds, might be candidate drugs for the treatment of acute ischemic strokes, and 3d may be a promising therapeutic agent for the primary and secondary prevention of ischemic stroke.

No MeSH data available.


Related in: MedlinePlus

Tissue distribution of 3d in mice after 10 mg/kg intravenous administration at 15, 45, and 90 minutes, including heart, liver, spleen, lung, kidney, and brain tissue.Note: Data were expressed as the mean ± SD (n=6).Abbreviation: SD, standard deviation.
© Copyright Policy
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4492651&req=5

f11-dddt-9-3377: Tissue distribution of 3d in mice after 10 mg/kg intravenous administration at 15, 45, and 90 minutes, including heart, liver, spleen, lung, kidney, and brain tissue.Note: Data were expressed as the mean ± SD (n=6).Abbreviation: SD, standard deviation.

Mentions: After tail vein administration of 3d at a dosage of 10 mg/kg to KM mice (18–22 g), the mean concentrations of 3d in heart, liver, spleen, lung, kidney, and brain tissues at 15, 45, and 90 minutes are shown in Figure 11. The figure showed that compound 3d distributed rapidly into various tissues after tail vein administration, the concentrations reaching the maxima in all organs at 15 minutes postdose, and the concentrations of 3d in brain rapidly increasing and then gradually declining, similar to that in liver. All these results demonstrated that 3d could be rapidly absorbed and penetrate the brain through blood–brain barrier in mice.


Discovery of 3-n-butyl-2,3-dihydro-1H-isoindol-1-one as a potential anti-ischemic stroke agent.

Lan Z, Xu X, Xu W, Li J, Liang Z, Zhang X, Lei M, Zhao C - Drug Des Devel Ther (2015)

Tissue distribution of 3d in mice after 10 mg/kg intravenous administration at 15, 45, and 90 minutes, including heart, liver, spleen, lung, kidney, and brain tissue.Note: Data were expressed as the mean ± SD (n=6).Abbreviation: SD, standard deviation.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4492651&req=5

f11-dddt-9-3377: Tissue distribution of 3d in mice after 10 mg/kg intravenous administration at 15, 45, and 90 minutes, including heart, liver, spleen, lung, kidney, and brain tissue.Note: Data were expressed as the mean ± SD (n=6).Abbreviation: SD, standard deviation.
Mentions: After tail vein administration of 3d at a dosage of 10 mg/kg to KM mice (18–22 g), the mean concentrations of 3d in heart, liver, spleen, lung, kidney, and brain tissues at 15, 45, and 90 minutes are shown in Figure 11. The figure showed that compound 3d distributed rapidly into various tissues after tail vein administration, the concentrations reaching the maxima in all organs at 15 minutes postdose, and the concentrations of 3d in brain rapidly increasing and then gradually declining, similar to that in liver. All these results demonstrated that 3d could be rapidly absorbed and penetrate the brain through blood–brain barrier in mice.

Bottom Line: This activity is superior to that of 3-n-butylphthalide and comparable with aspirin and edaravone.Meanwhile, 3d not only exhibited a potent activity in scavenging free radicals and improving the survival of HT22 cells against the reactive oxygen species-mediated cytotoxicity in vitro but also significantly attenuated the ischemia/reperfusion-induced oxidative stress in ischemic rat brains.In conclusion, our findings suggest that 3-alkyl-2,3-dihydro-1H-isoindol-1-ones, a novel series of compounds, might be candidate drugs for the treatment of acute ischemic strokes, and 3d may be a promising therapeutic agent for the primary and secondary prevention of ischemic stroke.

View Article: PubMed Central - PubMed

Affiliation: School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, People's Republic of China.

ABSTRACT
To develop novel anti-ischemic stroke agents with better therapeutic efficacy and bioavailability, we designed and synthesized a series of 3-alkyl-2,3-dihydro-1H-isoindol-1-ones compounds (3a-i) derivatives, one of which (3d) exhibited the strongest inhibitory activity for the adenosine diphosphate-induced and arachidonic acid-induced platelet aggregation. This activity is superior to that of 3-n-butylphthalide and comparable with aspirin and edaravone. Meanwhile, 3d not only exhibited a potent activity in scavenging free radicals and improving the survival of HT22 cells against the reactive oxygen species-mediated cytotoxicity in vitro but also significantly attenuated the ischemia/reperfusion-induced oxidative stress in ischemic rat brains. Results from transient middle cerebral artery occlusion and permanent middle cerebral artery occlusion model, indicated that 3d could significantly reduce infarct size, improve neurobehavioral deficits, and prominently decrease attenuation of cerebral damage. Most importantly, 3d possessed a very high absolute bioavailability and was rapidly distributed in brain tissue to keep high plasma drug concentration for the treatment of ischemic strokes. In conclusion, our findings suggest that 3-alkyl-2,3-dihydro-1H-isoindol-1-ones, a novel series of compounds, might be candidate drugs for the treatment of acute ischemic strokes, and 3d may be a promising therapeutic agent for the primary and secondary prevention of ischemic stroke.

No MeSH data available.


Related in: MedlinePlus