Q1 · MEDICINE
Article
Author: Sakurada, Isao ; Mancuso, Jessica Y. ; Smith, Deborah L. ; Hou, Xinjun ; Houle, Christopher ; Boscoe, Brian P. ; Lazzaro, John T. ; Barricklow, Jason ; Walker, Daniel P. ; Coffman, Karen J. ; Chen, Laigao ; Chenard, Lois K. ; Drozda, Susan E. ; Cianfrogna, Julie ; Tuttle, Jamison B. ; Trapa, Patrick ; Reese, Matthew R. ; Karki, Kapil ; Miller, Emily L. ; Dunetz, Joshua R. ; Wright, Ann S. ; Balan, Gayatri ; Marcek, John M. ; Whritenour, Jessica ; Stepan, Antonia F. ; Barreiro, Gabriela ; O’Neil, Steven ; Skaddan, Marc ; Shaffer, Christopher L. ; Zasadny, Kenneth ; Zhang, Lei ; Claffey, Michelle M. ; Cappon, Gregg D. ; Moen, Mark A. ; Parikh, Vinod ; Zaleska, Margaret M. ; Ghosh, Somraj ; Bohanon, Michael J. ; Won, Annie ; Verhoest, Patrick R.
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.