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.
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| Title: | 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. |
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| Authors: | Stepan AF; Neuroscience and Pain Medicinal Chemistry, ‡Pharmacokinetics, Dynamics, and Metabolism, and §Neuroscience and Pain Research Unit, Pfizer Inc. , Cambridge, Massachusetts 02139, United States.; 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., Claffey MM; Neuroscience and Pain Medicinal Chemistry, ‡Pharmacokinetics, Dynamics, and Metabolism, and §Neuroscience and Pain Research Unit, Pfizer Inc. , Cambridge, Massachusetts 02139, United States.; 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., Reese MR; Neuroscience and Pain Medicinal Chemistry, ‡Pharmacokinetics, Dynamics, and Metabolism, and §Neuroscience and Pain Research Unit, Pfizer Inc. , Cambridge, Massachusetts 02139, United States.; 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., Balan G; Neuroscience and Pain Medicinal Chemistry, ‡Pharmacokinetics, Dynamics, and Metabolism, and §Neuroscience and Pain Research Unit, Pfizer Inc. , Cambridge, Massachusetts 02139, United States.; 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., Barreiro G; Neuroscience and Pain Medicinal Chemistry, ‡Pharmacokinetics, Dynamics, and Metabolism, and §Neuroscience and Pain Research Unit, Pfizer Inc. , Cambridge, Massachusetts 02139, United States.; 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., Barricklow J; Neuroscience and Pain Medicinal Chemistry, ‡Pharmacokinetics, Dynamics, and Metabolism, and §Neuroscience and Pain Research Unit, Pfizer Inc. , Cambridge, Massachusetts 02139, United States.; 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., Bohanon MJ; Neuroscience and Pain Medicinal Chemistry, ‡Pharmacokinetics, Dynamics, and Metabolism, and §Neuroscience and Pain Research Unit, Pfizer Inc. , Cambridge, Massachusetts 02139, United States.; 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., Boscoe BP; Neuroscience and Pain Medicinal Chemistry, ‡Pharmacokinetics, Dynamics, and Metabolism, and §Neuroscience and Pain Research Unit, Pfizer Inc. , Cambridge, Massachusetts 02139, United States.; 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., Cappon GD; Neuroscience and Pain Medicinal Chemistry, ‡Pharmacokinetics, Dynamics, and Metabolism, and §Neuroscience and Pain Research Unit, Pfizer Inc. , Cambridge, Massachusetts 02139, United States.; 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., Chenard LK; Neuroscience and Pain Medicinal Chemistry, ‡Pharmacokinetics, Dynamics, and Metabolism, and §Neuroscience and Pain Research Unit, Pfizer Inc. , Cambridge, Massachusetts 02139, United States.; 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., Cianfrogna J; Neuroscience and Pain Medicinal Chemistry, ‡Pharmacokinetics, Dynamics, and Metabolism, and §Neuroscience and Pain Research Unit, Pfizer Inc. , Cambridge, Massachusetts 02139, United States.; 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., Chen L; Neuroscience and Pain Medicinal Chemistry, ‡Pharmacokinetics, Dynamics, and Metabolism, and §Neuroscience and Pain Research Unit, Pfizer Inc. , Cambridge, Massachusetts 02139, United States.; 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., Coffman KJ; Neuroscience and Pain Medicinal Chemistry, ‡Pharmacokinetics, Dynamics, and Metabolism, and §Neuroscience and Pain Research Unit, Pfizer Inc. , Cambridge, Massachusetts 02139, United States.; 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., Drozda SE; Neuroscience and Pain Medicinal Chemistry, ‡Pharmacokinetics, Dynamics, and Metabolism, and §Neuroscience and Pain Research Unit, Pfizer Inc. , Cambridge, Massachusetts 02139, United States.; 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., Dunetz JR; Neuroscience and Pain Medicinal Chemistry, ‡Pharmacokinetics, Dynamics, and Metabolism, and §Neuroscience and Pain Research Unit, Pfizer Inc. , Cambridge, Massachusetts 02139, United States.; 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., Ghosh S; Neuroscience and Pain Medicinal Chemistry, ‡Pharmacokinetics, Dynamics, and Metabolism, and §Neuroscience and Pain Research Unit, Pfizer Inc. , Cambridge, Massachusetts 02139, United States.; 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., Hou X; Neuroscience and Pain Medicinal Chemistry, ‡Pharmacokinetics, Dynamics, and Metabolism, and §Neuroscience and Pain Research Unit, Pfizer Inc. , Cambridge, Massachusetts 02139, United States.; 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., Houle C; Neuroscience and Pain Medicinal Chemistry, ‡Pharmacokinetics, Dynamics, and Metabolism, and §Neuroscience and Pain Research Unit, Pfizer Inc. , Cambridge, Massachusetts 02139, United States.; 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., Karki K; Neuroscience and Pain Medicinal Chemistry, ‡Pharmacokinetics, Dynamics, and Metabolism, and §Neuroscience and Pain Research Unit, Pfizer Inc. , Cambridge, Massachusetts 02139, United States.; 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., Lazzaro JT; Neuroscience and Pain Medicinal Chemistry, ‡Pharmacokinetics, Dynamics, and Metabolism, and §Neuroscience and Pain Research Unit, Pfizer Inc. , Cambridge, Massachusetts 02139, United States.; 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., Mancuso JY; Neuroscience and Pain Medicinal Chemistry, ‡Pharmacokinetics, Dynamics, and Metabolism, and §Neuroscience and Pain Research Unit, Pfizer Inc. , Cambridge, Massachusetts 02139, United States.; 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., Marcek JM; Neuroscience and Pain Medicinal Chemistry, ‡Pharmacokinetics, Dynamics, and Metabolism, and §Neuroscience and Pain Research Unit, Pfizer Inc. , Cambridge, Massachusetts 02139, United States.; 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., Miller EL; Neuroscience and Pain Medicinal Chemistry, ‡Pharmacokinetics, Dynamics, and Metabolism, and §Neuroscience and Pain Research Unit, Pfizer Inc. , Cambridge, Massachusetts 02139, United States.; 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., Moen MA; Neuroscience and Pain Medicinal Chemistry, ‡Pharmacokinetics, Dynamics, and Metabolism, and §Neuroscience and Pain Research Unit, Pfizer Inc. , Cambridge, Massachusetts 02139, United States.; 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., O'Neil S; Neuroscience and Pain Medicinal Chemistry, ‡Pharmacokinetics, Dynamics, and Metabolism, and §Neuroscience and Pain Research Unit, Pfizer Inc. , Cambridge, Massachusetts 02139, United States.; 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., Sakurada I; Neuroscience and Pain Medicinal Chemistry, ‡Pharmacokinetics, Dynamics, and Metabolism, and §Neuroscience and Pain Research Unit, Pfizer Inc. , Cambridge, Massachusetts 02139, United States.; 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., Skaddan M; Neuroscience and Pain Medicinal Chemistry, ‡Pharmacokinetics, Dynamics, and Metabolism, and §Neuroscience and Pain Research Unit, Pfizer Inc. , Cambridge, Massachusetts 02139, United States.; 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., Parikh V; Neuroscience and Pain Medicinal Chemistry, ‡Pharmacokinetics, Dynamics, and Metabolism, and §Neuroscience and Pain Research Unit, Pfizer Inc. , Cambridge, Massachusetts 02139, United States.; 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., Smith DL; Neuroscience and Pain Medicinal Chemistry, ‡Pharmacokinetics, Dynamics, and Metabolism, and §Neuroscience and Pain Research Unit, Pfizer Inc. , Cambridge, Massachusetts 02139, United States.; 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., Trapa P; Neuroscience and Pain Medicinal Chemistry, ‡Pharmacokinetics, Dynamics, and Metabolism, and §Neuroscience and Pain Research Unit, Pfizer Inc. , Cambridge, Massachusetts 02139, United States.; 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., Tuttle JB; Neuroscience and Pain Medicinal Chemistry, ‡Pharmacokinetics, Dynamics, and Metabolism, and §Neuroscience and Pain Research Unit, Pfizer Inc. , Cambridge, Massachusetts 02139, United States.; 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., Verhoest PR; Neuroscience and Pain Medicinal Chemistry, ‡Pharmacokinetics, Dynamics, and Metabolism, and §Neuroscience and Pain Research Unit, Pfizer Inc. , Cambridge, Massachusetts 02139, United States.; 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., Walker DP; Neuroscience and Pain Medicinal Chemistry, ‡Pharmacokinetics, Dynamics, and Metabolism, and §Neuroscience and Pain Research Unit, Pfizer Inc. , Cambridge, Massachusetts 02139, United States.; 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., Won A; Neuroscience and Pain Medicinal Chemistry, ‡Pharmacokinetics, Dynamics, and Metabolism, and §Neuroscience and Pain Research Unit, Pfizer Inc. , Cambridge, Massachusetts 02139, United States.; 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., Wright AS; Neuroscience and Pain Medicinal Chemistry, ‡Pharmacokinetics, Dynamics, and Metabolism, and §Neuroscience and Pain Research Unit, Pfizer Inc. , Cambridge, Massachusetts 02139, United States.; 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., Whritenour J; Neuroscience and Pain Medicinal Chemistry, ‡Pharmacokinetics, Dynamics, and Metabolism, and §Neuroscience and Pain Research Unit, Pfizer Inc. , Cambridge, Massachusetts 02139, United States.; 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., Zasadny K; Neuroscience and Pain Medicinal Chemistry, ‡Pharmacokinetics, Dynamics, and Metabolism, and §Neuroscience and Pain Research Unit, Pfizer Inc. , Cambridge, Massachusetts 02139, United States.; 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., Zaleska MM; Neuroscience and Pain Medicinal Chemistry, ‡Pharmacokinetics, Dynamics, and Metabolism, and §Neuroscience and Pain Research Unit, Pfizer Inc. , Cambridge, Massachusetts 02139, United States.; 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., Zhang L; Neuroscience and Pain Medicinal Chemistry, ‡Pharmacokinetics, Dynamics, and Metabolism, and §Neuroscience and Pain Research Unit, Pfizer Inc. , Cambridge, Massachusetts 02139, United States.; 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., Shaffer CL; Neuroscience and Pain Medicinal Chemistry, ‡Pharmacokinetics, Dynamics, and Metabolism, and §Neuroscience and Pain Research Unit, Pfizer Inc. , Cambridge, Massachusetts 02139, United States.; 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. |
| Source: | Journal of medicinal chemistry [J Med Chem] 2017 Sep 28; Vol. 60 (18), pp. 7764-7780. Date of Electronic Publication: 2017 Sep 13. |
| Publication Type: | Journal Article; Research Support, Non-U.S. Gov't |
| Journal Info: | Publisher: American Chemical Society Country of Publication: United States NLM ID: 9716531 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1520-4804 (Electronic) Linking ISSN: 00222623 NLM ISO Abbreviation: J Med Chem Subsets: MEDLINE |
| Database: | MEDLINE Ultimate |
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