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

• Published in: Journal of medicinal chemistry Vol. 60; no. 18; pp. 7764 - 7780
• Main Authors: Stepan, Antonia F, Claffey, Michelle M, Reese, Matthew R, Balan, Gayatri, Barreiro, Gabriela, Barricklow, Jason, Bohanon, Michael J, Boscoe, Brian P, Cappon, Gregg D, Chenard, Lois K, Cianfrogna, Julie, Chen, Laigao, Coffman, Karen J, Drozda, Susan E, Dunetz, Joshua R, Ghosh, Somraj, Hou, Xinjun, Houle, Christopher, Karki, Kapil, Lazzaro, John T, Mancuso, Jessica Y, Marcek, John M, Miller, Emily L, Moen, Mark A, O’Neil, Steven, Sakurada, Isao, Skaddan, Marc, Parikh, Vinod, Smith, Deborah L, Trapa, Patrick, Tuttle, Jamison B, Verhoest, Patrick R, Walker, Daniel P, Won, Annie, Wright, Ann S, Whritenour, Jessica, Zasadny, Kenneth, Zaleska, Margaret M, Zhang, Lei, Shaffer, Christopher L
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 28.09.2017; Amer Chemical Soc
• Subjects: Allosteric Regulation - drug effects; Animals; Chemistry, Medicinal; Female; HEK293 Cells; Heterocyclic Compounds, 3-Ring - adverse effects; Heterocyclic Compounds, 3-Ring - chemistry; Heterocyclic Compounds, 3-Ring - pharmacokinetics; Heterocyclic Compounds, 3-Ring - pharmacology; Humans; Life Sciences & Biomedicine; Male; Molecular Docking Simulation; Pharmacology & Pharmacy; Pyridines - adverse effects; Pyridines - chemistry; Pyridines - pharmacokinetics; Pyridines - pharmacology; Rats; Rats, Sprague-Dawley; Receptor, Metabotropic Glutamate 5 - antagonists & inhibitors; Receptor, Metabotropic Glutamate 5 - metabolism; Science & Technology; Structure-Activity Relationship; MEDICINAL CHEMISTRY; ANTAGONIST; CLINICAL DEVELOPMENT; ANXIOLYTIC-LIKE; BASIMGLURANT; MGLU5 RECEPTOR; TOXICITY; BLOCKADE; DRUG TARGETS; PREDICTION
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/acs.jmedchem.7b00604

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 required to confirm this and determine clinical relevance.