Systematic Approach for Screening of Prodrugs: Evaluation Using Oseltamivir Analogues as Models

Prodrug development is a common approach in drug development. In a recent study, we established a systematic strategy for selecting prodrugs with improved membrane permeability or solubility based on log D value, solubility in artificial intestinal fluids, membrane permeability, and metabolic instability. The purpose of this study was to evaluate the utility of this strategy using oseltamivir and 23 kinds of oseltamivir analogues having various types of side chain as well as their active metabolite, oseltamivir acid. Log D values of oseltamivir and analogues (2.0 to 4.9) were higher than that of oseltamivir acid (0.7), supporting the previous development of oseltamivir to improve permeability of oseltamivir acid. Solubilities of analogues in artificial intestinal fluids were over 80%, except the compound with the highest lipophilicity. Positive correlation was observed between membrane permeability and log D values of analogues. In metabolic profiles, species differences in the hydrolysis efficiency were observed depending on analogues. Using our strategy, it was demonstrated that oseltamivir and some analogues are appropriate prodrugs that could be advanced to in vivo pharmacokinetic studies, with selection of suitable animals. This study confirmed the utility of our strategy for narrowing down of candidate compounds to proceed into in vivo study.