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,Journal of Medicinal Chemistry

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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
Journal of Medicinal Chemistry ( IF 7.3 ) Pub Date : 2017-09-13 00:00:00 , DOI: 10.1021/acs.jmedchem.7b00604
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}

Affiliation

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.

中文翻译：

（R）-6-新戊基-2-（吡啶-2-基甲氧基）-6,7-二氢嘧啶基[2,1- c ] [1,4]恶嗪-4（9 H）-one（PF -06462894），在大鼠和非人类灵长类动物中都存在的缺乏炔烃的代谢型谷氨酸受体5负变构调节剂

我们先前观察到非人类灵长类动物（NHP）中具有mGlu ₅阴性变构调节剂（NAM）7的皮肤IV型免疫反应。为了确定这种不良事件是基于化学型还是基于机制，我们评估了一系列不同的mGlu ₅ NAM。增加高通量筛选命中率40的sp ³特性，提供了新的吗啉代嘧啶酮mGlu ₅ NAM系列。其原型为（R）-6-新戊基-2-（吡啶-2-基甲氧基）-6,7-二氢嘧啶基[2,1- c ] [1,4]恶嗪-4（9 H）-一（PF- 06462894，8），具有良好的特性，并具有较低的预计临床剂量（每天两次两次2 mg）。在小鼠药物过敏模型中，化合物8没有显示任何免疫激活的迹象。此外，来自毒理学研究的血浆样本证实了8种没有形成任何反应性代谢产物。然而，有8例在NHP中引起了与7例相同的微观皮肤病变，尽管严重程度较低。从整体上看，这项工作支持以下假说：这种独特的毒性可能是基于机制的，尽管还需要其他工作来确认这一点并确定临床相关性。

更新日期：2017-09-13

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