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

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS

卷:26

Article

Conde-Ceide, Susana¹  Alcazar, Jesus¹  Alonso de Diego, Sergio A.¹  Lopez, Silvia¹  Luz Martin-Martin, Maria¹  Martinez-Viturro, Carlos M.¹  Pena, Miguel-Angel¹  Min Tong, Han¹  Lavreysen, Hilde²  Mackie, Claire³  Bridges, Thomas M.^4,5  Daniels, J. Scott^4,5  Niswender, Colleen M.^4,5  Jones, Carrie K.^4,5  Macdonald, Gregor J.²  Steckler, Thomas²  Conn, P. Jeffrey^4,5  Stauffer, Shaun R.^4,5  Lindsley, Craig W.^4,5  Manuel Bartolome-Nebreda, Jose¹ 

[1] Janssen Res & Dev, Neurosci Med Chem, Toledo 45007, Spain

[2] Janssen Res & Dev, Neurosci, B-2340 Beerse, Belgium

[3] Janssen Res & Dev, Discovery Sci ADME Tox, B-2340 Beerse, Belgium

[4] Vanderbilt Univ, Med Ctr, Vanderbilt Ctr Neurosci Drug Discovery, Nashville, TN 37232 USA

[5] Vanderbilt Univ, Med Ctr, Dept Pharmacol, Nashville, TN 37232 USA

关键词: Metabotropic glutamate receptor;    mGlu(5);    N-Methyl-D-aspartate (NMDA);    Positive allosteric modulator (PAM);    Schizophrenia;   

DOI  :  10.1016/j.bmcl.2015.11.098

来源: Elsevier

【 摘 要 】

As part of our efforts to identify a suitable back-up compound to our recently disclosed mGlu(5) 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 mGlu(5) 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 mGlu(5) activation and target-related toxicities. (C) 2015 Elsevier Ltd. All rights reserved.

【 授权许可】

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