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The design, synthesis, pharmacokinetic and pharmacodynamic evaluation of acyloxyalkyl-substituted T705 prodrugs

Author(s):

Xingzhou Li, Tianhong Zhang and Wu Zhong  

Abstract:


Background: The pharmacokinetic properties of T705 are not optimal for the development of new drugs.

Objective: To improve the pharmacokinetic properties of T-705, structure modification of T-705 was conducted using a prodrug strategy.

Method: The acidic amide H atom (N4-H) of T705 was attempted to be replaced with acyloxyalkyl groups following the prodrugs development strategy for carboxylic acids, and the resulting compounds were investigated whether could work as prodrugs and contribute to improving the pharmacokinetic properties of the parent compound T705 in vivo.

Results: 4-acyloxyalkyl-T705 (4a–e), did act as prodrugs in vivo. 4-iso-butyryloxymethyl-T705 (4a) and 4-acetoxymethyl-T705 (4b) could significantly improve the plasma concentration and systemic exposure for T705, compound 4a displayed non inferior anti-influenza activities, compared with its parent drug T705.

Conclusion: Our prodrugs development strategy for T705 is feasible, which may serves as a reference to prodrugs development of similar heterocyclic amides compounds.

Keywords:

favipiravir, T705, prodrug, anti-influenza virus, blood concentration, systemic exposure

Affiliation:

Beijing Institute of Pharmacology and Toxicology, 27 Taiping Road, Beijing 100850, PR , Beijing Institute of Pharmacology and Toxicology, 27 Taiping Road, Beijing 100850, PR , Beijing Institute of Pharmacology and Toxicology, 27 Taiping Road, Beijing 100850, PR



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