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

doi:10.1021/acs.jmedchem.7b00604

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

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

Authors

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

¹ Neuroscience and Pain Medicinal Chemistry, ‡Pharmacokinetics, Dynamics, and Metabolism, and §Neuroscience and Pain Research Unit, Pfizer Inc. , Cambridge, Massachusetts 02139, United States.
² Pharmaceutical Sciences, ⊥Pharmacokinetics, Dynamics, and Metabolism, #Biostatistics, Early Clinical Development, ∇Drug Safety Research and Development, and ○BioImaging Center, Pfizer Inc. , Groton, Connecticut 06340, United States.

PMID: 28817277
DOI: 10.1021/acs.jmedchem.7b00604

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Allosteric Regulation / drug effects*
Animals
Female
HEK293 Cells
Heterocyclic Compounds, 3-Ring / adverse effects
Heterocyclic Compounds, 3-Ring / chemistry
Heterocyclic Compounds, 3-Ring / pharmacokinetics*
Heterocyclic Compounds, 3-Ring / pharmacology*
Humans
Male
Molecular Docking Simulation
Pyridines / adverse effects
Pyridines / chemistry
Pyridines / pharmacokinetics*
Pyridines / pharmacology*
Rats
Rats, Sprague-Dawley
Receptor, Metabotropic Glutamate 5 / antagonists & inhibitors*
Receptor, Metabotropic Glutamate 5 / metabolism*
Structure-Activity Relationship

Substances

Heterocyclic Compounds, 3-Ring
PF-06462894
Pyridines
Receptor, Metabotropic Glutamate 5