Discovery and Preclinical Characterization of 1-Methyl-3-(4-methylpyridin-3-yl)-6-(pyridin-2-ylmethoxy)-1<i>H</i>-pyrazolo-[3,4-<i>b</i>]pyrazine (PF470): A Highly Potent, Selective, and Efficacious Metabotropic Glutamate Receptor 5 (mGluR5) Negative Allosteric Modulator

Zhang, Lei; Balan, Gayatri; Barreiro, Gabriela; Boscoe, Brian P.; Chenard, Lois K.; Cianfrogna, Julie; Claffey, Michelle M.; Chen, Laigao; Coffman, Karen J.; Drozda, Susan E.; Dunetz, Joshua R.; Fonseca, Kari R.; Galatsis, Paul; Grimwood, Sarah; Lazzaro, John T.; Mancuso, James P.; Miller, Emily; Reese, Matthew R.; Rogers, Bruce N.; Sakurada, Isao; Skaddan, Marc B.; Smith, Deborah L.; Stepan, Antonia F.; Trapa, Patrick; Tuttle, Jamison B.; Verhoest, Patrick R.; Walker, Daniel P.; Wright, Ann S.; Zaleska, Margaret M.; Zasadny, Kenneth R.; Shaffer, Christopher L.

doi:10.1021/jm401622k

Cited by 50 publications

(47 citation statements)

References 26 publications

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“…Several in vitro and in vivo studies have supported the putative involvement of mGluR-mediated signaling on progression, aggressiveness, and recurrence of malignant gliomas, which points to the notion that specific subtype-selective mGluR ligands may be considered as potential adjuvant chemotherapy for glioma treatment. Several academic groups [116–118], Pfizer [119], Roche [120, 121], Novartis [122] and Merck [123] have employed receptor structure-based design of mGluR selective negative allosteric modulators (NAMs) in their studies and ligand-receptor binding models were refined using mutagenesis and structure-activity data. Even though pharmaceutical and toxicological properties of all mGluR ligands are not yet entirely determined for humans (such as effective and maximum tolerable doses), several clinical studies on Phase I, II and III are being performed using mGluR modulators for treatment of distinct brain disorders and cancer.…”

Section: Discussionmentioning

confidence: 99%

Metabotropic glutamate receptors as a new therapeutic target for malignant gliomas

et al. 2017

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Metabotropic glutamate receptors (mGluR) are predominantly involved in maintenance of cellular homeostasis of central nervous system. However, evidences have suggested other roles of mGluR in human tumors. Aberrant mGluR signaling has been shown to participate in transformation and maintenance of various cancer types, including malignant brain tumors. This review intends to summarize recent findings regarding the involvement of mGluR-mediated intracellular signaling pathways in progression, aggressiveness, and recurrence of malignant gliomas, mainly glioblastomas (GBM), highlighting the potential therapeutic applications of mGluR ligands. In addition to the growing number of studies reporting mGluR gene or protein expression in glioma samples (resections, lineages, and primary cultures), pharmacological blockade in vitro of mGluR1 and mGluR3 by selective ligands has been shown to be anti-proliferative and anti-migratory, decreasing activation of MAPK and PI3K pathways. In addition, mGluR3 antagonists promoted astroglial differentiation of GBM cells and also enabled cytotoxic action of temozolomide (TMZ). mGluR3-dependent TMZ toxicity was supported by increasing levels of MGMT transcripts through an intracellular signaling pathway that sequentially involves PI3K and NF-?B. Further, continuous pharmacological blockade of mGluR1 and mGluR3 have been shown to reduced growth of GBM tumor in two independent in vivo xenograft models. In parallel, low levels of mGluR3 mRNA in GBM resections may be a predictor for long survival rate of patients. Since several Phase I, II and III clinical trials are being performed using group I and II mGluR modulators, there is a strong scientifically-based rationale for testing mGluR antagonists as an adjuvant therapy for malignant brain tumors.

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Section: Discussionmentioning

confidence: 99%

Metabotropic glutamate receptors as a new therapeutic target for malignant gliomas

et al. 2017

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“…Pfizer has reported an instance of biliary epithelial hyperplasia in a NHP toxicology study with an alkyne-based mGlu 5 NAM developed by Wyeth. 35 This toxicity was believed to be linked to the reactivity of the alkyne based on metabolic studies that revealed extensive glutathione conjugation. 35 While this type of biotransformation does not always manifest in humans with alkyne-containing compounds, 25,27 many research groups have sought to design novel mGlu 5 NAMs that are outside of this chemotype.…”

Section: Introductionmentioning

confidence: 99%

“…35 This toxicity was believed to be linked to the reactivity of the alkyne based on metabolic studies that revealed extensive glutathione conjugation. 35 While this type of biotransformation does not always manifest in humans with alkyne-containing compounds, 25,27 many research groups have sought to design novel mGlu 5 NAMs that are outside of this chemotype. 4,5 We have actively pursued a variety of approaches toward that end over the past decade.…”

Section: Introductionmentioning

confidence: 99%

Discovery of N-(5-Fluoropyridin-2-yl)-6-methyl-4-(pyrimidin-5-yloxy)picolinamide (VU0424238): A Novel Negative Allosteric Modulator of Metabotropic Glutamate Receptor Subtype 5 Selected for Clinical Evaluation

et al. 2017

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Preclinical evidence in support of the potential utility of mGlu5 NAMs for the treatment of a variety of psychiatric and neurodegenerative disorders is extensive, and multiple such molecules have entered clinical trials. Despite some promising results from clinical studies, no small molecule mGlu5 NAM has yet to reach market. Here we present the discovery and evaluation of N-(5-fluoropyridin-2-yl)-6-methyl-4-(pyrimidin-5-yloxy)picolinamide (27, VU0424238), a compound selected for clinical evaluation. Compound 27 is more than 900-fold selective for mGlu5 versus the other mGlu receptors, and binding studies established a Ki value of 4.4 nM at a known allosteric binding site. Compound 27 had a clearance of 19.3 and 15.5 mL/min/kg in rats and cynomolgus monkeys, respectively. Imaging studies using a known mGlu5 PET ligand demonstrated 50% receptor occupancy at an oral dose of 0.8 mg/kg in rats and an intravenous dose of 0.06 mg/kg in baboons.

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“…There is evidence for MPEP effects on NR2B-containing NMDA receptors [37], which may explain its inhibition of the development of opioid tolerance. There remains interest in developing therapeutic negative allosteric modulators that selectively target mGluR5 [14; 65]. However, higher doses of systemically delivered MPEP (100 mg/kg) and the analog MTEP (30–100 mg/kg) resulted in reduction of locomotor activity and impairment of rotarod performance[68].…”

Section: Discussionmentioning

confidence: 99%

Bivalent ligand that activates mu opioid receptor and antagonizes mGluR5 receptor reduces neuropathic pain in mice

Peterson

Kitto

Akgün

et al. 2017

Pain

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The mu opioid receptor (MOR) and metabotropic glutamate receptor 5 (mGluR5) are well-established pharmacological targets in the management of chronic pain. Both receptors are expressed in spinal cord. MMG22, a bivalent ligand containing two pharmacophores separated by 22 atoms that simultaneously activates MOR and antagonizes mGluR5 has been shown to produce potent reversal of tactile hypersensitivity in rodent models of LPS- and bone-cancer-induced chronic pain. The present study assessed whether intrathecal MMG22 also is effective in reducing pain of neuropathic origin. Further, we theorized that MMG22 should reduce hyperalgesia in nerve-injured mice in a manner consistent with a synergistic interaction between MOR and mGluR5. Several weeks following spared nerve injury, tactile hypersensitivity was reversed in mice by intrathecal injection of MMG22 (0.01–10 nmol) but also by its shorter spacer analog, MMG10, with similar potency. The potencies of the bivalent ligands were 10-14-fold higher than those of the compounds upon which the bivalent structure was based, the MOR agonist oxymorphone and the mGluR5 antagonist MPEP. Co-administration of oxymorphone and MPEP demonstrated analgesic synergism, an interaction confirmed by isobolographic analysis. The present study indicates that in the spared nerve-injury induced model of neuropathic pain, the two pharmacophores of the bivalent ligands MMG22 and MMG10 target MOR and mGluR5 as separate receptor monomers. The observed increase in potency of MMG22 and MMG10, compared to oxymorphone and MPEP, may reflect the synergistic interaction of the two pharmacophores of the bivalent ligand acting at their respective separate receptor monomers.

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Discovery and Preclinical Characterization of 1-Methyl-3-(4-methylpyridin-3-yl)-6-(pyridin-2-ylmethoxy)-1H-pyrazolo-[3,4-b]pyrazine (PF470): A Highly Potent, Selective, and Efficacious Metabotropic Glutamate Receptor 5 (mGluR5) Negative Allosteric Modulator

Cited by 50 publications

References 26 publications

Metabotropic glutamate receptors as a new therapeutic target for malignant gliomas

Metabotropic glutamate receptors as a new therapeutic target for malignant gliomas

Discovery of N-(5-Fluoropyridin-2-yl)-6-methyl-4-(pyrimidin-5-yloxy)picolinamide (VU0424238): A Novel Negative Allosteric Modulator of Metabotropic Glutamate Receptor Subtype 5 Selected for Clinical Evaluation

Bivalent ligand that activates mu opioid receptor and antagonizes mGluR5 receptor reduces neuropathic pain in mice

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