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首页> 外文期刊>Antimicrobial agents and chemotherapy. >CS-8958, a prodrug of the novel neuraminidase inhibitor R-125489, demonstrates a favorable long-retention profile in the mouse respiratory tract.
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CS-8958, a prodrug of the novel neuraminidase inhibitor R-125489, demonstrates a favorable long-retention profile in the mouse respiratory tract.

机译：CS-8958是新型神经氨酸酶抑制剂R-125489的前药，在小鼠呼吸道中显示出良好的长期保留特征。

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摘要

CS-8958 is a prodrug of the pharmacologically active form R-125489, a selective neuraminidase inhibitor, and has long-acting anti-influenza virus activity in vivo. In this study, the tissue distribution profiles after a single intranasal administration of CS-8958 (0.5 micromol/kg of body weight) to mice were investigated, focusing especially on the retention of CS-8958 in the respiratory tract by comparing it with R-125489 and a marketed drug, zanamivir. After administration of [(14)C]CS-8958, radioactivity was retained in the respiratory tract over long periods. At 24 h postdose, the radioactivity concentrations after administration of [(14)C]CS-8958 were approximately 10-fold higher in both the trachea and the lung than those of [(14)C]R-125489 and [(14)C]zanamivir. The [(14)C]CS-8958-derived radioactivity present in these two tissues consisted both of unchanged CS-8958 and of R-125489 at 1 h postdose, while only R-125489, and no other metabolites, was detected at 24 h postdose. After administration of unlabeled CS-8958, CS-8958 was rapidly eliminated from the lungs, whereas the lung R-125489 concentration reached a maximum at 3 h postdose and gradually declined, with an elimination half-life of 41.4 h. The conversion of CS-8958 to R-125489 was observed in mouse trachea and lung S9 fractions and was inhibited by esterase inhibitors, such as diisopropylfluorophosphate and bis-p-nitrophenylphosphate. These results demonstrated that CS-8958 administered intranasally to mice was efficiently converted to R-125489 by a hydrolase(s) such as carboxylesterase, and then R-125489 was slowly eliminated from the respiratory tract. These data support the finding that CS-8958 has potential as a long-acting neuraminidase inhibitor, leading to significant efficacy as an anti-influenza drug by a single treatment.
机译：CS-8958是R-125489（选择性神经氨酸酶抑制剂）的药理活性形式的前药，在体内具有长效抗流感病毒活性。在这项研究中，研究了对小鼠单次鼻内施用CS-8958（0.5微摩尔/千克体重）后的组织分布状况，特别是将CS-8958与R-进行比较，重点研究了CS-8958在呼吸道中的保留情况。 125489和市售药物扎那米韦。给予[（14）C] CS-8958后，放射性长时间保留在呼吸道中。给药后24小时，[[14] C] CS-8958的给药后，气管和肺部的放射性浓度比[（14）C] R-125489和[（14））高约10倍。 C]扎那米韦。给药后1小时，这两种组织中存在的[（14）C] CS-8958衍生的放射性均由未改变的CS-8958和R-125489组成，而在第24小时仅检测到R-125489，没有其他代谢物h服药后。施用未标记的CS-8958后，CS-8958被迅速从肺中清除，而肺R-125489的浓度在给药后3小时达到最大值，然后逐渐下降，消除半衰期为41.4 h。在小鼠气管和肺S9级分中观察到CS-8958向R-125489的转化，并被酯酶抑制剂（例如二异丙基氟磷酸酯和双-对硝基苯基磷酸酯）抑制。这些结果表明，鼻内施用给小鼠的CS-8958被水解酶例如羧酸酯酶有效地转化为R-125489，然后R-125489从呼吸道中被缓慢消除。这些数据支持以下发现：CS-8958具有作为长效神经氨酸酶抑制剂的潜力，从而通过单次治疗即可作为抗流感药物产生显着疗效。

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