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. 2017 Sep 28;60(18):7764-7780.
doi: 10.1021/acs.jmedchem.7b00604. Epub 2017 Sep 13.

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

Antonia F Stepan  1   2 , Michelle M Claffey  1   2 , Matthew R Reese  1   2 , Gayatri Balan  1   2 , Gabriela Barreiro  1   2 , Jason Barricklow  1   2 , Michael J Bohanon  1   2 , Brian P Boscoe  1   2 , Gregg D Cappon  1   2 , Lois K Chenard  1   2 , Julie Cianfrogna  1   2 , Laigao Chen  1   2 , Karen J Coffman  1   2 , Susan E Drozda  1   2 , Joshua R Dunetz  1   2 , Somraj Ghosh  1   2 , Xinjun Hou  1   2 , Christopher Houle  1   2 , Kapil Karki  1   2 , John T Lazzaro  1   2 , Jessica Y Mancuso  1   2 , John M Marcek  1   2 , Emily L Miller  1   2 , Mark A Moen  1   2 , Steven O'Neil  1   2 , Isao Sakurada  1   2 , Marc Skaddan  1   2 , Vinod Parikh  1   2 , Deborah L Smith  1   2 , Patrick Trapa  1   2 , Jamison B Tuttle  1   2 , Patrick R Verhoest  1   2 , Daniel P Walker  1   2 , Annie Won  1   2 , Ann S Wright  1   2 , Jessica Whritenour  1   2 , Kenneth Zasadny  1   2 , Margaret M Zaleska  1   2 , Lei Zhang  1   2 , Christopher L Shaffer  1   2
Affiliations

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

Antonia F Stepan et al. J Med Chem. .

Abstract

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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