94193-78-9Relevant articles and documents
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
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.
, p. 7764 - 7780 (2017/10/10)
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.
Diastereoselective synthesis of novel 5-substituted morpholine-3-phosphonic acids: Further exploitation of N-acyliminium intermediates
Bonilla-Landa, Israel,Viveros-Ceballos, José Luis,Ordó?ez, Mario
, p. 485 - 487 (2014/05/06)
The first diastereoselective total synthesis of 5-substituted morpholine-3-phosphonic acids is reported. The principal feature of the synthesis is the introduction of a dimethyl phosphonate group into 5-substituted morpholin-3-ones. The procedure is based
Amine-promoted asymmetric (4+2) annulations for the enantioselective synthesis of tetrahydropyridines: A traceless and recoverable auxiliary strategy
Hu, Pengfei,Hu, Jian,Jiao, Jiajun,Tong, Xiaofeng
supporting information, p. 5319 - 5322 (2013/06/05)
Gone, without a trace: The in situ reaction of 2-(acetoxymethyl)buta-2,3- dienoate and a secondary amine produces a 2-methylene-3-oxobutanoate equivalent that can be used in asymmetric [4+2] annulations with N-tosylimines to provide tetrahydropyridines in
