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

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-through...