C. Bonnefous et al. / Bioorg. Med. Chem. Lett. 15 (2005) 1197–1200
1199
Figure 1. Important hydrogen binding motifs of mGlu5 antagonists.
that could engage in an internal hydrogen bonding inter-
action with the amide oxygen (20, 26, and 31). This SAR
tracks with the pyrazine series (Table 1). Compound 31
was the second most potent analog synthesized in this
series and reveals that there is ample space for substitu-
tion at the R1 position. Also there may be additional
opportunities to improve potency by substitution with
aromatic groups or with hydrogen bond acceptors. Fur-
ther SAR revealed that removal of the other pyrazine
nitrogen atom (22) or both (23) led to complete loss of
activity (Fig. 1). However, both heteroatoms could be
removed without a significant loss of potency, as long
as one substituent on the phenyl ring could engage in
an internal hydrogen bonding interaction with the
amide carbonyl as seen in 24. Additionally, the N-
methyl derivative 18 (Fig. 1) is inactive, indicating that
the amide NH bonding interaction may be the more
important of the two, however other considerations
such as sterics and rotamer population may be overrid-
ing factors in this case. Based on the SAR conducted in
both the pyrazine and pyridine series, we postulate that
these molecules require at least one (21 and 24) or even
better, two critical internal hydrogen bonding interac-
tions (20, 26, and 31) to achieve the proper conforma-
tion for binding to the mGlu5 receptor (Fig. 1).
In summary, high throughput screening identified 2 as a
structurally distinct mGlu5 receptor antagonist with
modest in vitro potency. Optimization of the lead led
to the discovery of new compounds (16 and 20) in this
class, with potencies comparable to MTEP (1).
Although initial pharmacokinetic evaluations suggest
that these compounds are rapidly cleared from plasma,
they may have some use in evaluating the role of mGlu5
in animal models of diseases.
Acknowledgements
The authors thank Merryl Cramer and Christopher
King for expert technical assistance.
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Table 3. Pharmacokinetic parameters of selected compounds
Compd
13
20
31
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Clp (ml/min/kg)a
t1/2 (iv, h)a
56
4.4
20
>100
<LOQd
<LOQd
176
1.25
NDc
%F (po)b
a Iv dosing at 2 mg/kg.
b Po dosing at 10 mg/kg.
c ND: not determined.
d LOQ: limit of quantitation.