Synthesis and biological evaluation of hybrids from optically active ring-opened 3-N-butylphthalide derivatives and 4-fluro-edaravone as potential anti-acute ischemic stroke agents.
Bioorg Med Chem
; 69: 116891, 2022 09 01.
Article
em En
| MEDLINE
| ID: mdl-35764031
ABSTRACT
The treatment of acute ischemic stroke (AIS) remains a tough challenge in clinic. Here, we report the anti-AIS activity of R- and S-FMPB generated from hybridization of ring-opened R- and S-3-N-butylphthalide (R- and S-NBP) derivatives (R- and S-APB) with 4-fluro-edaravone (4-F-Eda), respectively. S-FMPB (10 mg/kg, iv) significantly improved the neurological score and alleviated cerebral infarction and edema of rats suffered from transient middle cerebral artery occlusion (tMCAO), superior to RS- and R-FMPB, as well as better than RS-FMPB by oral administration in previous studies. Importantly, S-FMPB is more active not only than the equimolar S-APB and 4-F-Eda alone or in combination but also than the clinical drugs NBP and edaravone (Eda) in combination at the equimolar doses. Furthermore, S-FMPB showed relative stability in plasma or liver microsome of rats but could be converted into two active metabolites (S-NBP and 4-F-Eda) in rats with good pharmacokinetic properties in terms of longer half-life period (t1/2) and mean residence time (MRT) as well as larger area under the concentration-time curve (AUC) of S-NBP than those from S-NBP and 4-F-Eda single or in combination by iv administration, suggesting that S-NBP and 4-F-Eda may synergistically play the anti-AIS activity. Our findings suggest that S-FMPB may be used as a potential anti-AIS agent to further study.
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Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Benzofuranos
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Fármacos Neuroprotetores
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Acidente Vascular Cerebral
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AVC Isquêmico
Limite:
Animals
Idioma:
En
Revista:
Bioorg Med Chem
Assunto da revista:
BIOQUIMICA
/
QUIMICA
Ano de publicação:
2022
Tipo de documento:
Article
País de afiliação:
China