H. Tye et al. / Bioorg. Med. Chem. Lett. 21 (2011) 34–37
37
Figure 2. Data for compound (7g) and Lorcaserin in the 3 day cafeteria diet model.
in Caco-2 permeability compared to earlier analogues. Conse-
quently these analogues were not considered to be suitable for
further profiling.
At this stage we were looking to identify a suitable tool com-
pound to establish whether compounds of this structural class
would be efficacious in vivo. Despite its high level of hERG inhibi-
hERG ion channel. Whilst some compounds, bearing polar side
chains did show a much reduced hERG liability this came at the ex-
pense of potency and permeability. Further research efforts are fo-
cussed on identifying compounds which are not limited by such off
target activity issues.
tion (0.4 lM in manual patch-clamp) 4-MeO analogue (7g) showed
References and notes
the best overall profile. It met the potency and selectivity criteria
we had set based on its in vitro profile (<100 nM 5-HT2C, weak
partial agonism at 5-HT2A and 5-HT2B) and it was found to be
neutral at 5-HT2A and an antagonist at 5-HT2B in ex vivo tissue
assays.10,11 In addition this compound exhibited an excellent rat
PK profile (Table 3) having low clearance and long exposure after
oral administration (MRT >24 h). Based on the good CSF/Plasma-
unbound ratio of 0.15 we expected this compound to be brain pe-
netrant and therefore effective in vivo.
Compound (7g) was found to efficacious in a 3 day weight loss
experiment where the compound was administered orally to rats
fed on a so-called ‘cafeteria’ chocolate based diet. Statistically sig-
nificant weight loss of 3.3% (P = 0.0014) relative to the cafeteria fed
control group was observed at a dose of 100 mg/kg which com-
pared well to the 3.2% (P = 0.06) weight loss observed with Lorcas-
erin dosed at 30 mg/kg (Fig. 2).
Female Wistar rats (ex-breeder; n = 6 each group) were fed a
cafeteria diet for three consecutive days. The diet consisted of dif-
ferent chocolate bars and cookies add libitum on top of standard
chow diet. Animals were randomized to body weight at day one.
Compound 7g, Lorcaserin, and vehicle control (0.5% natrosol) was
applied once daily (po application) and body weight was assessed
every day. Control chow received standard chow diet only.
In summary we have identified a novel series of 5-HT2C agonists
based on a tricyclic pyrazolopyrimidine scaffold. Compounds with
good levels of in vitro potency and moderate to good levels of
selectivity with respect to the 5-HT2A and 5-HT2B receptors were
identified. One of the analogues (7g) was found to be efficacious
in a sub-chronic weight loss model. However a key limitation of
the series of compounds was found to be their inhibition of the
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