CS-8958, a Prodrug of the Novel Neuraminidase Inhibitor R-125489, Demonstrates a Favorable Long-Retention Profile in the Mouse Respiratory Tract
CS-8958, a Prodrug of the Novel Neuraminidase Inhibitor R-125489, Demonstrates a Favorable Long-Retention Profile in the Mouse Respiratory Tract
复制标题
DOI：
10.1128/aac.00731-09
复制
发表时间：
2009-11-01
影响因子：
4.9
通讯作者：
Okazaki, Osamu
中科院分区：
文献类型：
--
作者：
Koyama, Kumiko;Takahashi, Makoto;Okazaki, Osamu
CS-8958 是药理活性形式 R-125489 的前药，R-125489 是一种选择性神经氨酸酶抑制剂，在体内具有长效抗流感病毒活性。本研究对小鼠单次鼻内给药 CS-8958（0.5 μmol/kg 体重）后的组织分布情况进行了研究，通过与 R-125489 和市售药物扎那米韦进行比较，特别关注 CS-8958 在呼吸道中的滞留情况。给予[(14)C]CS-8958后，放射性在呼吸道中保留很长时间。给药后24小时，给予[(14)C]CS-8958后，气管和肺中的放射性浓度比[(14)C]R-125489和[(14)C]扎那米韦的放射性浓度高约10倍。给药后 1 小时，这两种组织中存在的 [(14)C]CS-8958 衍生放射性由未变化的 CS-8958 和 R-125489 组成，而给药后 24 小时仅检测到 R-125489，没有检测到其他代谢物。给予未标记的CS-8958后，CS-8958迅速从肺部消除，而肺部R-125489浓度在给药后3小时达到最大值并逐渐下降，消除半衰期为41.4小时。在小鼠气管和肺 S9 部分中观察到 CS-8958 转化为 R-125489，并被酯酶抑制剂（例如二异丙基氟磷酸盐和双对硝基苯磷酸盐）抑制。这些结果表明，给小鼠鼻内施用的CS-8958通过水解酶例如羧酸酯酶有效地转化为R-125489，然后R-125489从呼吸道缓慢消除。这些数据支持这样的发现：CS-8958 具有作为长效神经氨酸酶抑制剂的潜力，通过单次治疗即可产生显着的抗流感药物疗效。
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 mu mol/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.