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for inhibition against a panel of the major cytochrome
P450 isoforms, imidazole 10 did not inhibit any
CYP isoforms at the test concentration (IC50Õs >
14lM)—specifically the CYP 1A2 IC50 = 70lM. In
contrast, pyridine 8, although not inhibitory against
3A4, 2D6, 2C9, 2C19, inhibits CYP 1A2 with
IC50 = 2.3lM.
Both compounds showed high rat receptor occupancy
(97%) when dosed at 10mg/kg intraperitoneally (meas-
uring at 1h). Furthermore at this time point the brain
levels of 8 and 10 were 9.7 and 8.1lM, respectively, indi-
cating both compounds were highly brain penetrant. In
comparing rat pharmacokinetics, both compounds are
bioavailable (%F = 22–24%), however, imidazole 10 suf-
fers from a short high-life (t1/2 = 0.3h) and high clear-
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B.; Anderson, J.; Brodkin, J.; Chung, J.; Jiang, X.; King,
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13. The selectivity of the prototypical tetrazole 2 was deter-
mined by extensive profiling against a battery of in vitro
assays (MDS Pharma Services screen). In addition, 2 is
highly selective for mGlu5 over mGlu1 (mGlu1 Ca2+ flux
IC50 > 10lM).
14. Ito, S.; Tanaka, Y.; Kakehi, K. Chem. Lett. 1973, 10,
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15. Poon, S. F.; Eastman, B. W.; Chapman, D. F.; Chung, J.;
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ance (Cl = 40mL/min/kg) when compared to 8 (t1/2
=
2.9h, Cl = 15mL/min/kg). Due to the short half-life in
rat, these 2-imidazolyl tetrazole compounds were not
developed further.
In conclusion, SAR studies have shown that replacing
the 2-pyridyl ring of the tetrazole class of mGlu5 recep-
tor antagonist with a 2-imidazolyl ring leads to com-
pounds that do not inhibit CYP 1A2 (nor any of the
other major CYP isoforms) while maintaining high po-
tency, selectivity and in vivo receptor occupancy. How-
ever, a short half-life in rat precluded these compounds
from further development.
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Acknowledgements
We would like to thank Bill Bray and Darlene Giracello
for expert technical assistance.
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