Journal of Medicinal Chemistry p. 7764 - 7780 (2017)
Update date:2022-08-17
Topics:
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.
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.
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