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 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), possessed favorable properties and a predicted low clinical dose (2 mg twice daily). Compound did not show any evidence of immune activation in a mouse drug allergy model. Additionally, plasma samples from toxicology studies confirmed that did not form any reactive metabolites. However, caused the identical microscopic skin lesions in NHPs found with, 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.