Preliminary investigation of 6,7-dihydropyrazolo[1,5-a]pyrazin-4-one derivatives as a novel series of mGlu5 receptor positive allosteric modulators with efficacy in preclinical models of schizophrenia

[Display omitted] As part of our efforts to identify a suitable back-up compound to our recently disclosed mGlu5 positive allosteric modulator (PAM) clinical candidate VU0490551/JNJ-46778212, this letter details the investigation and challenges of a novel series of 6,7-dihydropyrazolo[1,5-a]pyrazin-...

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Published in:Bioorganic & medicinal chemistry letters 2016-01, Vol.26 (2), p.429-434
Main Authors: Conde-Ceide, Susana, Alcázar, Jesús, Alonso de Diego, Sergio A., López, Silvia, Martín-Martín, María Luz, Martínez-Viturro, Carlos M., Pena, Miguel-Angel, Tong, Han Min, Lavreysen, Hilde, Mackie, Claire, Bridges, Thomas M., Daniels, J. Scott, Niswender, Colleen M., Jones, Carrie K., Macdonald, Gregor J., Steckler, Thomas, Conn, P. Jeffrey, Stauffer, Shaun R., Lindsley, Craig W., Bartolomé-Nebreda, José Manuel
Format: Article
Language:English
Subjects:
Allosteric Regulation - drug effects
Animals
Antipsychotic Agents - chemistry
Antipsychotic Agents - pharmacokinetics
Antipsychotic Agents - therapeutic use
HEK293 Cells
Humans
Male
Metabotropic glutamate receptor
mGlu5
N-Methyl-d-aspartate (NMDA)
Positive allosteric modulator (PAM)
Pyrazines - chemistry
Pyrazines - pharmacokinetics
Pyrazines - therapeutic use
Pyrazoles - chemistry
Pyrazoles - pharmacokinetics
Pyrazoles - therapeutic use
Rats, Sprague-Dawley
Receptor, Metabotropic Glutamate 5 - metabolism
Schizophrenia
Schizophrenia - drug therapy
Schizophrenia - metabolism
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Summary:[Display omitted] As part of our efforts to identify a suitable back-up compound to our recently disclosed mGlu5 positive allosteric modulator (PAM) clinical candidate VU0490551/JNJ-46778212, this letter details the investigation and challenges of a novel series of 6,7-dihydropyrazolo[1,5-a]pyrazin-4-one derivatives. From these efforts, compound 4k emerged as a potent and selective mGlu5 PAM displaying overall attractive in vitro (pharmacological and ADMET) and PK profiles combined with in vivo efficacy in preclinical models of schizophrenia. However, further advancement of the compound was precluded due to severely limiting CNS-related side-effects confirming the previously reported association between excessive mGlu5 activation and target-related toxicities.
ISSN:0960-894X
1464-3405
DOI:10.1016/j.bmcl.2015.11.098