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for advancement as a potential back-up candidate for 1.
Unfortunately, during a toxicology rat MTD study (25, 75, 150,
300 and 600 mg/kg, p.o.) evidence for signs for CNS-related
side-effects (compulsive behavior (chewing and head shaking),
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highest dose, precluded further development and confirmed again
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mGlu5.
In conclusion, as part of our efforts towards a back-up
compound for the mGlu5 PAM clinical candidate
1
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(VU0409551/JNJ-46778212) from a different chemotype, a
scaffold hopping strategy resulted in the identification of a series
of 6,7-dihydropyrazolo[1,5-a]pyrazin-4-ones as potent mGlu5
PAMs. SAR investigations within this chemotype resulted in the
identification of compound 4k as a potential back-up candidate.
Despite 4k possessing attractive in vitro and in vivo
pharmacological, ADMET and PK properties, rat toxicology
MTD studies deemed the compound inadequate for further
progression as a consequence of side-effects likely due to
excessive mGlu5 activation. Efforts aimed to identify less
efficacious mGlu5 PAMs, within this and other chemotypes will
be reported in due course.
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ill, M. J.; Robbins, T. W.;
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Figure 3. 4k has antipsychotic-like activity in male, Sprague Dawley rats.
4k dose-dependently (3-100 mg/kg, p.o.) reverses AHL. Vehicle is 20% HP-
-CD (3-10 mg/kg solution, 30-100 mg/kg suspension).
Acknowledgments
23. Bartolome-Nebreda, J.M.; Conde-Ceide, S.; Delgado, F.; Pastor, J.; Pena, M.A.;
Trabanco, A.A.; Tresadern, G.; Wassvik, C.M.; Stauffer, S.R.; Jadhav, S.; Days, E.;
Weaver, C.D.; Lindsley, C.W.; Niswender, C.M.; Jones, C.K.; Conn, P.J.;
Rombouts, F.; Lavreysen, H.; Macdonald, G.J.; Mackie, C.; Steckler, T. J. Med.
Chem. 2013, 56, 7243-7259.
24. Martin-Martin, M.L.; Bartolome-Nebreda, J.M.; Conde-Ceide, S.; Alonso, S.A.;
Lopez, S.; Martinez-Viturro, C.M.; Tong, H.M.; Lavreysen, H.; Macdonald, G.J.;
Steckler, T.; Mackie, C.; Daniels, S.J.; Niswender, C.M.; Jones, C.K.; Conn, P.J.;
Lindsley, C.W.; Stauffer, S.R. Bioorg. Med. Chem. Lett. 2015, 25, 1310-1317.
25. Compounds were tested for agonist, PAM or antagonist activity on mGlu receptors
in fluorescent Ca2+ assays using HEK293 cells expressing human mGlu1, mGlu2,
mGlu3, mGlu7 or mGlu8 receptors. Effects on the human mGlu4 receptor were tested
in Ca2+ or [35S]-GTPS functional assays (receptor either expressed in HEK293 or
L929sA cells). Evaluation of effects on the rat mGlu6 receptors expressed in CHO
cells were assessed in [35S]-GTPS functional assays.
26. Turlington, M.; Malosh, C.; Jacobs, J.; Manka, J.T.; Noetzel, M.J.; Vinson, P.N.;
Jadhav, S.; Herman, E.J.; Lavreysen, H.; Mackie, C.; Bartolome-Nebreda, J.M.;
Conde-Ceide, S.; Martin-Martin, M.L.; Tong, H.M.; Lopez, S.; Macdonald, G.J.;
Steckler, T.; Daniels, J.S.; Weaver, C.; Niswender, C.M.; Jones, C.; Conn, J.P.;
Lindsley, C.W.; Stauffer, S.R. J. Med. Chem. 2014, 57, 5620.
27. Wager, T.T.; Chandrasekaran, R.I.; Hou, X.; Troutman, M.D.; Verhoest, P.R.;
Villalobos, A.; Will, Y. ACS Chem. Neurosci. 2010, 1, 420.
The authors would like to thank Ms. Janire Lamariano and Dr.
Sandra Luengo for their support in the synthesis of some
compounds described herein and Dr José-Manuel Alonso, Mr.
Alberto Fontana and Dr. Laura Iturrino for their help with the
analytical characterization of the compounds.
Supplementary Material
Synthesis and experimental details for 4k, synthesis routes and
general conditions used to prepare analogs 4z, 20 and 21a-c and
contextual fear conditioning data for 4k are available as
supplementary material.
References and notes
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