Lumicitabine (ALS-008176) (ALS-008176) 是呼吸道合胞病毒 (RSV) 聚合酶的抑制剂。
Lumicitabine (ALS-008176) is an inhibitor of the respiratory syncytial virus (RSV) polymerase.
Lumicitabine is an orally bioavailable prodrug of the novel RSV replication inhibitor ALS-008112, a cytidine nucleoside analogue[1].
Lumicitabine demonstrates excellent anti-RSV efficacy and safety in a phase 2 clinical RSV challenge study. It exhibits good oral bioavailability and a high level of 2c-TP in vivo. Lumicitabine has excellent stability profiles in formulations (>24 h storage stability in 0.5% methylcellulose aqueous formulation at rt) and simulats gastric and intestinal fluids (half-life >2 h). Its solubility is adequate to support oral administration in solutions with relatively low percentage of organic solvent and in aqueous suspensions. High levels of NMP and NTP are obtained following oral administration of Lumicitabine to monkeys[2]. In an adult human challenge study, Lumicitabine has shown efficacy against RSV infection[1].
[1]. DeVincenzo JP, et al. Activity of Oral ALS-008176 in a Respiratory Syncytial Virus Challenge Study. N Engl J Med. 2015 Nov 19;373(21):2048-58. [2]. Wang G, et al. Discovery of 4'-chloromethyl-2'-deoxy-3',5'-di-O-isobutyryl-2'-fluorocytidine (ALS-8176), a first-in-class RSV polymerase inhibitor for treatment of human respiratory syncytial virus infection. J Med Chem. 2015 Feb 26;58(4):1862-78.
Animal experiment: | Rats: Lumicitabine are formulated as solutions in PEG400-based vehicles. Pharmacokinetic studies are conducted at 5 mg/kg and for oral PK studies the prodrugs are administered at 5 mg/kg parent nucleoside equivalent doses. Blood samples are typically collected at various time points up to 24 h post dose for rat[2]. Monkeys: Lumicitabine are formulated as solutions in PEG400-based vehicles. Pharmacokinetic studies are conducted at 5 mg/kg and for oral PK studies the prodrugs are administered at 5 mg/kg parent nucleoside equivalent doses. Blood samples are typically collected at various time points up to 12 h post dose for Monkeys[2]. |
参考文献: [1]. DeVincenzo JP, et al. Activity of Oral ALS-008176 in a Respiratory Syncytial Virus Challenge Study. N Engl J Med. 2015 Nov 19;373(21):2048-58. | |
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