Y. Shirasaki et al. / Bioorg. Med. Chem. Lett. 18 (2008) 5174–5177
5177
In conclusion, we designed and synthesized the derivatives of
2 with various mEG chains in the P3 region as a model com-
pound to explore the structure modification for designing highly
retinal penetrable inhibitors. We have succeeded in producing 3
and 4 with 5.5-fold and 3-fold higher retinal exposures after
instillation of 1% solution, respectively, by optimization of mEG
chain in the P3 region. Extension of mEG chain length resulted
in an increase in aqueous solubility without a marked decrease
in lipophilicity. Adjustment of mEG chain length enabled com-
pounds to possess optimal physicochemical properties for intra-
ocular absorption. So far, the relationships between retinal
exposure and aqueous humor exposure are not yet fully under-
stood; however, we were able to show the positive correlation
in at least this series of compounds. The intraocular exposure
after instillation of this series did not significantly correlate with
the plasma drug exposure after oral administration. This indi-
cated that each absorption process has each optimal balance be-
tween hydrophilicity and lipophilicity. These result showed that
incorporation of a mEG chain in compounds would be a useful
and convenient approach to attain high intraocular penetration
and oral absorption. We expect that this approach will be uti-
lized for future drug designs for the treatment of retinal
diseases.
1
2
3
4
2.5
2
1.5
1
0.5
0
3
4
0
1
2
Time (h)
Figure 4. Plasma drug levels after oral administration of 0.2% suspension or
solution in 0.5% carboxymethyl cellulose solution to cynomolgus monkeys. The
values represent the mean SD (n = 3–6).
structure modification method, because it can easily adjust the bal-
ance between lipophilicity and hydrophilicity.
It is expected that 3 could show neuroprotective efficacy in a rat
acute ocular hypertension model. In the previous study, 2 showed
neuroprotective efficacy in this pharmacological model at an oral
dose of 120 mg/kg.15 The retinal levels after oral 10 mg/kg dose
in rats are 0.4
tion, respectively.14 Therefore, the effective retinal drug levels in
this model should range from 2.5 to 5 M. Although the maximum
retinal levels of 2 after instillation was 1.2 M, the retinal level of 3
was 6.3 M at Tmax and was at least more than 2.5 M at 4 h after
instillation.
lM and 0.2 lM at Tmax and at 4 h after administra-
Acknowledgments
l
The authors thank Drs. Akira Ohtori and Hideyuki Sakaki for
reading this manuscript. In addition, we thank Mr. Tetsuya Tajika
for useful discussions.
l
l
l
To investigate the relationships between the intraocular expo-
sure via instillation and the plasma exposure via oral administra-
tion of this series of compounds (1–4), the plasma drug levels
after oral administration of them (10 mg/kg) to cynomolgus mon-
keys were measured. The results are shown in Table 2 and Figure 4.
The optimal properties of compounds for oral exposure differed
from that for the intraocular exposures. Compound 2 showed the
highest plasma exposure among them. However, alteration of the
mEG chain length did not produce remarkable differences in plas-
ma exposure (AUC0–4h). The plasma exposure via oral dosing in-
volves various factors including metabolism, stability in
gastrointestinal tract, and so on. In the case of oral administration,
administrated compounds received more body fluid exposure and
longer residence time in gastrointestinal tract and can contact to
more areas for absorption compared to topical instillation. Due to
these differences, the optimal property for ocular exposure did
not correlate with that for oral plasma exposure. It was supposed
that 2 had sufficient aqueous solubility and adequate lipophilicity
for oral absorption. Since plasma exposure after oral administra-
tion of these compounds possessing an oligoethylene glycol chain
was higher than that of the related derivatives containing other
similar non-ionic amphiphiles such as tetrahydrofuran and tetra-
hydropyran moieties,13 introduction of a mEG chain is effective
in enhancing oral absorption. Furthermore, since variation of a
mEG length can simply optimize the balance between hydrophilic-
ity and lipophilicity, it could easily maximize oral absorption.
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