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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

Plasma concentration–time curves after 10 mg/kg iv administration and 10 mg/kg po administration of 3d.Note: Data were expressed as the mean ± SD (n=6).Abbreviations: IV, intravenous; po, orally; SD, standard deviation.
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f10-dddt-9-3377: Plasma concentration–time curves after 10 mg/kg iv administration and 10 mg/kg po administration of 3d.Note: Data were expressed as the mean ± SD (n=6).Abbreviations: IV, intravenous; po, orally; SD, standard deviation.

Mentions: An ideal anti-ischemic stroke drug should be quickly absorbed into blood circulation and permeate the cerebral infarction tissues following oral administration. The plasma concentration-time profiles of 3d are shown in Figure 10. These are obtained following oral administration or iv injection of 10 mg/kg of 3d in Wistar rats. As shown in Table 3, the AUC (min×µg/mL) of oral dose (10 mg/kg) and iv injection dose (10 mg/kg) were 770.6±19.6 and 821.5±41.9 min×µg/mL, respectively. The ∼90% absolute bioavailability observed suggested that most of the compound 3d was absorbed into the intestine, which might make up for the deficiency of NBP with its low bioavailability. The pharmacokinetic parameters were calculated by different compartment model fitting using the WinNonlin software.


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)

Plasma concentration–time curves after 10 mg/kg iv administration and 10 mg/kg po administration of 3d.Note: Data were expressed as the mean ± SD (n=6).Abbreviations: IV, intravenous; po, orally; SD, standard deviation.
© Copyright Policy
Related In: Results  -  Collection

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

f10-dddt-9-3377: Plasma concentration–time curves after 10 mg/kg iv administration and 10 mg/kg po administration of 3d.Note: Data were expressed as the mean ± SD (n=6).Abbreviations: IV, intravenous; po, orally; SD, standard deviation.
Mentions: An ideal anti-ischemic stroke drug should be quickly absorbed into blood circulation and permeate the cerebral infarction tissues following oral administration. The plasma concentration-time profiles of 3d are shown in Figure 10. These are obtained following oral administration or iv injection of 10 mg/kg of 3d in Wistar rats. As shown in Table 3, the AUC (min×µg/mL) of oral dose (10 mg/kg) and iv injection dose (10 mg/kg) were 770.6±19.6 and 821.5±41.9 min×µg/mL, respectively. The ∼90% absolute bioavailability observed suggested that most of the compound 3d was absorbed into the intestine, which might make up for the deficiency of NBP with its low bioavailability. The pharmacokinetic parameters were calculated by different compartment model fitting using the WinNonlin software.

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