7006
S. C. Zammit et al. / Bioorg. Med. Chem. Lett. 19 (2009) 7003–7006
microsomes. Compounds were incubated with microsomes and
the loss of parent compound assessed by LC–MS analysis. Micro-
some-predicted intrinsic clearance values are shown in Table 1.
For the pair of homologous series 11, 12 and 14, and 19, 20
and 22, clearance rates increased with increasing substituent
chain length. Comparison of the regioisomeric pairs: 11 and 19;
12 and 20; and 14 and 22; shows that clearance rates are higher
for the 3-substituted series. Given that tranilast is in clinical use,
the observation of similar predicted metabolic stability for com-
pounds 11 and 12 suggests that they are sufficiently stable to
merit further investigation.
Based on the activity data and the predicted intrinsic clearance
values, compound 11 was selected for preliminary bioavailability
studies. Varying amounts of compound 11 were given as a single
oral dose to Sprague-Dawley rats and blood plasma levels were as-
sessed by LC–MS. Maximal blood plasma levels were obtained 4 h
post oral, and significant amounts of 11 were still present 8 h after
dosing (Fig. 3).
The ability to reduce albuminuria was experimentally assessed
in a rat model of diabetic nephropathy (Fig. 4). Hypertensive Ren2
rats were exposed to streptozotocin to induce diabetes. After four
weeks of experimental diabetes, a 24 h urine collection was
assayed for albuminuria by radioimmunoassay. Untreated rats
developed significant albuminuria that was attenuated by oral
administration of 11 by oral gavage at 200 mg/kg/day. In contrast,
tranilast attenuates albuminuria only when administered at higher
doses of 400 mg/kg/day.16
In conclusion novel derivatives of the known antifibrotic, trani-
last (1), were prepared and assayed for their ability to inhibit TGF-b
in cultured mesangial cells. Several lipophilic derivatives possessed
increased activity relative to 1, especially compound 11, which also
showed excellent metabolic properties, and improved in vivo
activity. Compound 11 can reduce albuminuria in a hypertensive
diabetic rat model and therefore represents a promising lead in
the development of potential antifibrotic drugs.
Acknowledgment
We thank the National Health and Medical Research Council for
financial support. Denis Scanlon is thanked for HPLC analysis.
Supplementary data
Supplementary data associated with this article can be found, in
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