Discovery and Characterization of (R)-6-Neopentyl-2-(pyridin-2-ylmethoxy)-6,7-dihydropyrimido[2,1-c][1,4]oxazin-4(9H)-one (PF-06462894), an Alkyne-Lacking Metabotropic Glutamate Receptor 5 Negative Allosteric Modulator Profiled in both Rat and Nonhuman Primates
| Autor: | Daniel P. Walker, Antonia F. Stepan, Mark A. Moen, Gregg D. Cappon, Christopher Houle, Annie C Won, Joshua R. Dunetz, Michael John Bohanon, Lei Zhang, Marc B. Skaddan, Patrick Robert Verhoest, Susan E. Drozda, Xinjun Hou, Kenneth R. Zasadny, Julie Cianfrogna, Deborah L. Smith, Ann S. Wright, John T. Lazzaro, Steven Victor O'neil, Patrick Trapa, Emily Miller, Somraj Ghosh, Gabriela Barreiro, John M. Marcek, Margaret M. Zaleska, Jason Barricklow, Michelle Marie Claffey, Lois K. Chenard, Jessica Mancuso, Christopher L. Shaffer, Jessica Whritenour, Gayatri Balan, Brian P. Boscoe, Vinod D. Parikh, Karen J. Coffman, Laigao Chen, Isao Sakurada, Jamison B. Tuttle, Matthew R. Reese, Karki Kapil Kumar |
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| Rok vydání: | 2017 |
| Předmět: |
Male
0301 basic medicine Allosteric modulator Pyridines Receptor Metabotropic Glutamate 5 Alkyne Pharmacology 030226 pharmacology & pharmacy Rats Sprague-Dawley Structure-Activity Relationship 03 medical and health sciences 0302 clinical medicine Immune system Allosteric Regulation Drug Discovery Animals Humans Structure–activity relationship Receptor chemistry.chemical_classification Chemistry Metabotropic glutamate receptor 5 HEK 293 cells Rats Molecular Docking Simulation HEK293 Cells 030104 developmental biology Toxicity Molecular Medicine Female Heterocyclic Compounds 3-Ring |
| Zdroj: | Journal of Medicinal Chemistry. 60:7764-7780 |
| ISSN: | 1520-4804 0022-2623 |
| Popis: | We previously observed a cutaneous type IV immune response in nonhuman primates (NHP) with the mGlu5 negative allosteric modulator (NAM) 7. To determine if this adverse event was chemotype- or mechanism-based, we evaluated a distinct series of mGlu5 NAMs. Increasing the sp3 character of high-throughput screening hit 40 afforded a novel morpholinopyrimidone mGlu5 NAM series. Its prototype, (R)-6-neopentyl-2-(pyridin-2-ylmethoxy)-6,7-dihydropyrimido[2,1-c][1,4]oxazin-4(9H)-one (PF-06462894, 8), possessed favorable properties and a predicted low clinical dose (2 mg twice daily). Compound 8 did not show any evidence of immune activation in a mouse drug allergy model. Additionally, plasma samples from toxicology studies confirmed that 8 did not form any reactive metabolites. However, 8 caused the identical microscopic skin lesions in NHPs found with 7, albeit with lower severity. Holistically, this work supports the hypothesis that this unique toxicity may be mechanism-based although additional work is require... |
| Databáze: | OpenAIRE |
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