Discovery of 3-Cyclopropylmethyl-7-(4-phenylpiperidin-1-yl)-8-trifluoromethyl[1,2,4]triazolo[4,3-<i>a</i>]pyridine (JNJ-42153605): A Positive Allosteric Modulator of the Metabotropic Glutamate 2 Receptor

Cid, José M.; Tresadern, Gary; Vega, Javier Martínez; Lucas, Ana I. De; Matesanz, Encarnación; Iturrino, Laura; Linares, María Lourdes; García, Aránzazu; Andrés, Juvenal; Macdonald, Gregor; Oehlrich, Daniel; Lavreysen, Hilde; Megens, Anton; Ahnaou, A.; Drinkenburg, Wilhelmus; Mackie, Claire; Pype, Stefan; Gallacher, David J.; Trabanco, Andrés A.

doi:10.1021/jm3010724

Cited by 79 publications

(51 citation statements)

References 43 publications

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“…A subsequent publication detailed continued optimization within this series in the context of a 4-phenylpiperidine substituent at the C 7 position (Figure 5) and described the discovery of JNJ-42153605 ( 61 ). 273 In this case, a triazolopyridine core was used as a less lipophilic alternative to the imidazopyridine. Critical to the success of this effort was the identification of the trifluoromethyl group at the C 8 position as an optimal substituent for mGlu 2 PAM activity.…”

Section: 2 Allosteric Modulators Of the Mglu2 And Mglu3 Receptorsmentioning

confidence: 99%

Practical Strategies and Concepts in GPCR Allosteric Modulator Discovery: Recent Advances with Metabotropic Glutamate Receptors

et al. 2016

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Allosteric modulation of GPCRs has initiated a new era of basic and translational discovery, filled with therapeutic promise yet fraught with caveats. Allosteric ligands stabilize unique conformations of the GPCR that afford fundamentally new receptors, capable of novel pharmacology, unprecedented subtype selectivity, and unique signal bias. This review provides a comprehensive overview of the basics of GPCR allosteric pharmacology, medicinal chemistry, drug metabolism, and validated approaches to address each of the major challenges and caveats. Then, the review narrows focus to highlight recent advances in the discovery of allosteric ligands for metabotropic glutamate receptor subtypes 1–5 and 7 (mGlu 1–57) highlighting key concepts (“molecular switches”, signal bias, heterodimers) and practical solutions to enable the development of tool compounds and clinical candidates. The review closes with a section on late-breaking new advances with allosteric ligands for other GPCRs and emerging data for endogenous allosteric modulators.

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Section: 2 Allosteric Modulators Of the Mglu2 And Mglu3 Receptorsmentioning

confidence: 99%

Practical Strategies and Concepts in GPCR Allosteric Modulator Discovery: Recent Advances with Metabotropic Glutamate Receptors

et al. 2016

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“…With stronger metabolic stability, another PAM, JNJ-42153605 effectively reversed PCP-induced hyperlocomotion (Cid et al, 2012). In addition, it has been reported that JNJ-40068782 was able to potentiate the binding of mGluR2/3 agonists (Lavreysen et al, 2013).…”

Section: Overview Of More Selective Mglur2/3 Agonists: Potentials mentioning

confidence: 99%

Perspectives on the mGluR2/3 agonists as a therapeutic target for schizophrenia: Still promising or a dead end?

et al. 2015

Progress in Neuro-Psychopharmacology and Biological Psychiatry

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Group II metabotropic glutamate receptor (mGluR2/3) agonists once showed promise as non-dopaminergic antipsychotic drugs because of their efficacy in alleviating symptoms of schizophrenia (SZ) in both animal models and human patients. However, the recent failure of Phase III clinical trials dealt a huge blow to the scientific community and the aftershock of the setback in mGluR2/3 research can be felt everywhere from grant support and laboratory studies to paper publication. An immediate question raised is whether mGluR2/3 is still a promising therapeutic target for schizophrenia. Answering this question is not easy, but apparently a new strategy is needed. This article provides a focused review of literature on the study of mGluR2/3 agonists, especially on mGluR2/3 agonists’ mechanism of action and efficacy in both normal conditions and animal models of SZ, as well as clinical studies in human patients with the disease. We argue that the cellular and molecular actions of mGluR2/3 agonists, the distinct roles between mGluR2 and mGluR3, as well as their effects on different stages of the disease and different subpopulations of patients, remain incompletely studied. Until the mechanisms associated with mGluR2/3 are clearly elucidated and all treatment options are tested, it would be a great mistake to terminate the study of mGluR2/3 as a therapeutic target for schizophrenia. This review will thus shed light on the comprehensive features of the translational potential mGluR2/3 agonists as well as the need for further research into the more selective activation of mGluR2.

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“…In an attempt to differentiate between various compounds and mechanisms of action, we compared the effects of JNJ‐40411813, the mGlu2/3 receptor agonist LY404039, the selective mGlu2 PAM JNJ‐42153605 (Cid et al. ) and the 5HT 2A receptor antagonist ritanserin in animal models for antipsychotic activity and side effects. Since the preclinical observations with JNJ‐40411813 have led to its selection for clinical studies, the results are also discussed in light of clinical data available for this molecule.…”

Section: Introductionmentioning

confidence: 99%

Preclinical evaluation of the antipsychotic potential of the mGlu2‐positive allosteric modulator JNJ‐40411813

Lavreysen

Langlois

Donck

et al. 2015

Pharmacology Res & Perspec

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JNJ-40411813/ADX71149 (1-butyl-3-chloro-4-(4-phenylpiperidin-1-yl) pyridin-2(1H)-one) is a positive allosteric modulator (PAM) of the mGlu2 receptor, which also displays 5-Hydroxytryptamine (5HT2A) antagonism after administration in rodents due to a rodent-specific metabolite. JNJ-40411813 was compared with the orthosteric mGlu2/3 agonist LY404039 (4-amino-2-thiabicyclo [3.1.0] hexane-4,6-dicarboxylic acid 2,2-dioxide), the selective mGlu2 PAM JNJ-42153605 (3-(cyclopropylmethyl)-7-(4-phenylpiperidin-1-yl)-8-(trifluoromethyl)[1,2,4]triazolo[4,3-a]pyridine) and the 5HT2A antagonist ritanserin in rodent models for antipsychotic activity and potential side effects, attempting to differentiate between the various compounds and mechanisms of action. In mice, JNJ-40411813, JNJ-42153605, and LY404039 inhibited spontaneous locomotion and phencyclidine- and scopolamine-induced but not d-amphetamine-induced hyperlocomotion; the 5HT2A antagonist ritanserin inhibited only spontaneous locomotion and phencyclidine-induced hyperlocomotion. As measured by 2-deoxyglucose uptake, all compounds reversed memantine-induced brain activation in mice. The two mGlu2 PAMs and LY404039, but not ritanserin, inhibited conditioned avoidance behavior in rats. Like ritanserin, the mGlu2 ligands antagonized 2,5-dimethoxy-4-methylamphetamine-induced head twitches in rats. LY404039 but not the mGlu2 PAMs impaired rotarod performance in rats and increased the acoustic startle response in mice. Our results show that although 5HT2A antagonism has effect in some models, mGlu2 receptor activation is sufficient for activity in several animal models of antipsychotic activity. The mGlu2 PAMs mimicked the in vivo pharmacodynamic effects observed with LY404039 except for effects on the rotarod and acoustic startle, suggesting that they produce a primary activity profile similar to that of the mGlu2/3 receptor agonist while they can be differentiated based on their secondary activity profile. The results are discussed in light of clinical data available for some of these molecules, in particular JNJ-40411813.

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Discovery of 3-Cyclopropylmethyl-7-(4-phenylpiperidin-1-yl)-8-trifluoromethyl[1,2,4]triazolo[4,3-a]pyridine (JNJ-42153605): A Positive Allosteric Modulator of the Metabotropic Glutamate 2 Receptor

Cited by 79 publications

References 43 publications

Practical Strategies and Concepts in GPCR Allosteric Modulator Discovery: Recent Advances with Metabotropic Glutamate Receptors

Practical Strategies and Concepts in GPCR Allosteric Modulator Discovery: Recent Advances with Metabotropic Glutamate Receptors

Perspectives on the mGluR2/3 agonists as a therapeutic target for schizophrenia: Still promising or a dead end?

Preclinical evaluation of the antipsychotic potential of the mGlu2‐positive allosteric modulator JNJ‐40411813

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