The identification of novel orally active mGluR5 antagonist GSK2210875

Pilla, Maria; Andreoli, Michela; Tessari, Michela; Delle-Fratte, Sonia; Roth, Adelheid; Butler, Sharon; Brown, Fiona; Shah, Parita; Bettini, Ezio; Cavallini, Palmina; Benedetti, Roberto; Minick, Douglas J.; Smith, Paul W.; Tehan, Benjamin G.; D'Alessandro, Pier Luca; Lorthioir, Olivier; Ball, Catherine J.; Garzya, Vincenzo; Goodacre, Caroline J.; Watson, Stephen P.

doi:10.1016/j.bmcl.2010.09.120

Cited by 21 publications

(10 citation statements)

References 11 publications

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“…Recently, synthetic mGluR5 antagonists have been developed as potential drugs for CNS disorders that are induced by the hypersecretion of glutamate [ 11 , 31 , 32 ]. It has been reported that administration of MPEP and MTEP has been used to effectively treat pain symptoms, Parkinson’s disease, cognition disorder, depression, anxiety, and schizophrenia [ 16 , 17 ].…”

Section: Discussionmentioning

confidence: 99%

The Role of Metabotropic Glutamate Receptor 5 on the Stromal Cell-Derived Factor-1/CXCR4 System in Oral Cancer

et al. 2013

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We have demonstrated that blocking CXCR4 may be a potent anti-metastatic therapy for CXCR4-related oral cancer. However, as CXCR4 antagonists are currently in clinical use to induce the mobilization of hematopoietic stem cells, continuous administration as an inhibitor for the metastasis may lead to persistent leukocytosis. In this study, we investigated the novel therapeutic downstream target(s) of the SDF-1/CXCR4 system, using B88-SDF-1 cells, which have an autocrine SDF-1/CXCR4 system and exhibit distant metastatic potential in vivo. Microarray analysis revealed that 418 genes were upregulated in B88-SDF-1 cells. We identified a gene that is highly upregulated in B88-SDF-1 cells, metabotropic glutamate receptor 5 (mGluR5), which was downregulated following treatment with 1,1’ -[1,4-Phenylenebis(methylene)]bis-1,4,8,11-tetraazacyclotetradecane octahydrochloride (AMD3100), a CXCR4 antagonist. The upregulation of mGluR5 mRNA in the SDF-1/CXCR4 system was predominately regulated by the Ras-extracellular signal-regulated kinase (ERK)1/2 pathway. Additionally, the growth of B88-SDF-1 cells was not affected by the mGluR5 agonist (S)-3,5-DHPG (DHPG) or the mGluR5 antagonists 2-Methyl-6-(phenylethynyl)pyridine (MPEP) and 3-((2-Methyl-1,3-thiazol-4-yl)ethynyl)pyridine (MTEP). However, we observed that DHPG promoted B88-SDF-1 cell migration, whereas both MPEP and MTEP inhibited B88-SDF-1 cell migration. To assess drug toxicity, the antagonists were intraperitoneally injected into immunocompetent mice for 4 weeks. Mice injected with MPEP (5 mg/kg) and MTEP (5 mg/kg) did not exhibit any side effects, such as hematotoxicity, allergic reactions or weight loss. The administration of antagonists significantly inhibited the metastasis of B88-SDF-1 cells to the lungs of nude mice. These results suggest that blocking mGluR5 with antagonists such as MPEP and MTEP could prevent metastasis in CXCR4-related oral cancer without causing side effects.

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Section: Discussionmentioning

confidence: 99%

The Role of Metabotropic Glutamate Receptor 5 on the Stromal Cell-Derived Factor-1/CXCR4 System in Oral Cancer

et al. 2013

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“…An excellent example of a medicinal chemistry methylation strategy was reported by a team at GlaxoSmithKline during the optimization of mGluR5 antagonist 16 ( Figure 5). [37] Various patterns of methylation were explored on the thiazole ring, the benzylic carbon, and the carbamate nitrogen atom of a high-throughput screening hit. By "walking" methyl groups around the periphery of 15 the team was able to locate a 40 nm inhibitor with a methyl group on the thiazole and a chiral methyl group at the benzylic position.…”

Section: Methodsmentioning

confidence: 99%

“…A complementary approach would be to access the innately reactive CÀH bonds [57] and, to our knowledge, the only method to methylate such bonds are the additions of methyl radical to heterocycles first reported by Minisci (Scheme 5). [58] In 1971, it was demonstrated that the methyl radical generated from acetic acid by a silver salt and an oxidant adds into protonated heterocycles such as 2-methylisoquinoline (37). [59] Subsequently, a related methylation of camptothecin (39) by using ferrous sulfate and tert-butylhydroperoxide was achieved in good yield.…”

Section: Methodsmentioning

confidence: 99%

Profound Methyl Effects in Drug Discovery and a Call for New CH Methylation Reactions

2013

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The methyl group is one of the most commonly occurring carbon fragments in small-molecule drugs. This simplest alkyl fragment appears in more than 67 % of the top-selling drugs of 2011 and can modulate both the biological and physical properties of a molecule. This Review focuses on so-called magic methyl effects on binding potency, where the seemingly mundane change of CH to CMe improves the IC50 value of a drug candidate more than 100-fold. This discussion is followed by a survey of recent advances in synthetic chemistry that allow the direct methylation of C(sp(2) )H and C(sp(3) )H bonds. It is our hope that the relevance of the meager methyl group to drug discovery as presented herein will inspire reports on new CH methylation reactions.

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“…In order to investigate whether the generated model of the interaction of NAMs with mGlu 5 could be successfully extended to include non-aryl alkyne compounds, seven known structurally-diverse and clinically important NAMs lacking the arylalkyne moiety [31][32][33][34][35][36][37] (compounds 26-32 in Scheme 1) were docked in the homology model and the results were compared with those described for the other NAMs. Compounds were selected on the basis of structural diversity, potency, clinical relevance, and their ability to displace MPEP in competition experiments.…”

Section: Binding Modes Of Representative Non-aryl Alkyne Namsmentioning

confidence: 99%

Insights into the interaction of negative allosteric modulators with the metabotropic glutamate receptor 5: Discovery and computational modeling of a new series of ligands with nanomolar affinity

Anighoro

Graziani

Bettinelli

et al. 2015

Bioorganic & Medicinal Chemistry

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The identification of novel orally active mGluR5 antagonist GSK2210875

Cited by 21 publications

References 11 publications

The Role of Metabotropic Glutamate Receptor 5 on the Stromal Cell-Derived Factor-1/CXCR4 System in Oral Cancer

The Role of Metabotropic Glutamate Receptor 5 on the Stromal Cell-Derived Factor-1/CXCR4 System in Oral Cancer

Profound Methyl Effects in Drug Discovery and a Call for New CH Methylation Reactions

Insights into the interaction of negative allosteric modulators with the metabotropic glutamate receptor 5: Discovery and computational modeling of a new series of ligands with nanomolar affinity

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