In vivo Activity


In a number of cases in the research literature, improved half-life and tissue penetration are observed on alkylation of a quinolone agent [2]. This may once more be a result of alkylation serving to increase the lipophilicity of the quinolones. This phenomenon is exemplified by some of the agents in Figures 5 and 6 that possess long half-lives appropriate for once-daily dosing. Grepaflox-acin can be looked at as dimethylated ciprofloxacin; this molecular modification results in substantially improved lung levels in murine studies [104] and a 2.5-fold increase in half-life in humans, to 10.3 hr [2], appropriate for once-daily administration. Sparfloxacin, which bears two alkyl groups on the C-7 piperazine and an additional C-8 fluorine compared to its parent ciprofloxacin, fits this paradigm as well, with a half-life in humans of 17.6 hr [2]. Oral efficacy in murine studies was also found to be enhanced by the presence of the two methyl groups on the piperazine [35]. In addition to its other lipophilic substituents, the 5-amino group has been found to increase the lipophilicity of the agent compared to the des-amino analogue via comparison of the octanol-water partition coefficients (log P) [35]. Incorporation of the methyl oxime substituent of gemifloxacin provided a nearly 10-fold improvement in oral bioavailability in rat [26].

In the case of sitafloxacin, alkylation of the C-7 pyrrolidine sidechain with the spirocyclopropane improved pharmacokinetic performance, yielding an increased Cmax over the unsubstituted pyrrolidine in animal studies [105]. In this series, unlike some of those described previously, the alkylation did not affect antibacterial activity.

Prulifloxacin (Figure 8) represents an interesting case of temporary alkylation, via use of a prodrug. The parent piperazine NM394 exhibited good in vitro activity but poor oral absorption. Addition of the N-(5-methyl-2-oxo-1,3-dioxol-4-yl)-methyl group, which is cleaved off to regenerate the unsubstituted piperazinyl quinolone in vivo, increased Cmax and area under the curve (AUC) after oral administration by more than threefold in animal studies [106,107].

The most common position for adjustment of pharmacokinetics, as just evidenced, is on the C-7 substituent [108]. However, the naphthyridone nucleus has also been shown to yield pharmacokinetics improved over those of an 8-unsubstituted quinolone [5]. Trovafloxacin, which exhibits a half-life of 10 hr in humans [2], is one of the few newer quinolone agents that takes advantage of

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