Journal of Medicinal Chemistry
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white solid. mp = 234-242 °C . 1H NMR (DMSO-d6) δ 10.68 (s,
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ABBREVIATIONS
4
5
6
7
8
9
1H, benzoxazinone-NH), 8.22 (s, 1H, -NH-), 7.77 (d, 1H, J =
7.68 Hz, pyridine-H), 7.70 (d, 1H, J = 7.89 Hz, pyridine-H),
7.45 (d, 1H, J = 7.68 Hz, pyridine-H), 7.37 (t, 1H, J = 5.85 Hz,
-NH-), 6.80 (t, 1H, J = 7.89 Hz, Ar), 6.47 (d, 1H, J = 7.89 Hz,
Ar), 4.62 (s, 2H, benzoxazinone-CH2-), 4.57 (s, 2H, methylene-
CH2), 4.38 (d, 2H, J = 6.36 Hz, pyridine-CH2-NH-), 3.10 (t, 4H,
J = 5.31 Hz, piperidine-N-(CH2)2-), 2.32 (t, 4H, J = 5.31 Hz,
piperidine-(CH2)2CCH2). HRMS (FAB) calc. for C22H22F3N5O3
[M + H]+ 462.1753, found 462.1748.
TRPV1, transient receptor potential vanilloid 1; RTX,
resiniferatoxin, MPOU, 1-((2-(4-methylpiperidin-1-yl)-6-
(trifluoromethyl)pyridin-3-yl)methyl)-3-(3-oxo-3,4-dihydro-
2H-benzo[b][1,4]oxazin-8-yl)urea.
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1-((2-(4-Methylpiperidin-1-yl)-6-(trifluoromethyl)pyridin-
3-yl)methyl)-3-(3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-
8-yl)urea (12) To compound 11 (0.030 g, 0.065 mmol) in
MeOH (2 mL) was added 10% Pd/C (cat) and the mixture was
stirred at 40 ˚C for 3 h. The reaction mixture was then allowed
to warm to ambient temperature and filtered over Celite. The
combined filtrate was concentrated in vacuo. Purification by
column chromatography (EtOAc/ Hex 1:2) gave 12 (0.025 g),
83% yield as a white solid. mp = 228-236 °C. 1H NMR (DMSO-
d6) δ 10.67 (s, 1H, benzoxazinone-NH), 8.21 (s, 1H, -NH-), 7.76
(d, 1H, J = 7.68 Hz, pyridine-H), 7.70 (d, 1H, J = 7. 89 Hz, Ar),
7.44 (d, 1H, J = 7.50 Hz, pyridine-H), 7.37 (t, 1H, J = 5.85 Hz,
-NH-), 6.80 (t, 1H, J = 7.89 Hz, Ar), 6.47 (d, 1H, J = 7.89 Hz,
Ar), 4.62 (s, 2H, benzoxazinone-CH2-), 4.30 (s, 2H, pyridine-
CH2-NH-), 3.39-3.43 (m, 2H, , piperidine-N-(CH2)2-), 2.76 (t,
2H, J = 11.73 Hz, piperidine-N-(CH2)2-), 1.71 (d, 2H, J = 11.52
Hz, piperidine), 1.53 (bs, 1H piperidine-CHCH3), 1.27-1.34 (m,
2H, piperidine-(CH2)2CCH3), 3.33 (d, 3H, J = 6.21, piperidine-
CHCH3). HRMS (FAB) calc. for C22H24F3N5O3 [M + H]+
464.1909, found 464.1906.
Radiolabeling for [3H]MPOU. Compound 11 was
radiolabeled by Quotient Bioresearch (Cardiff, United
Kingdom) using reduction with tritium gas over a Pd/charcoal
catalyst. The specific activity obtained was 78 Ci/mmol, as
determined by mass spectroscopy. Purity was greater than 99.7%
as determined by HPLC against an authentic sample of non-
radiolabeled MPOU.
■ ASSOCIATED CONTENT
Supporting Information. The Supporting Information is
available free of charge on the ACS Publication website at DOI:
Purity of the final compounds, detailed experimental
procedures for binding assay and molecular formula strings.
■ AUTHOR INFORMATION
Corresponding Author
* Phone, 82-2-880-7846; E-mail, jeewoo@snu.ac.kr.
* Phone, 1-240-760-6632; E-mail,
Notes
The authors declare no competing financial interest.
# The authors contributed equally as first authors.
* The authors contributed equally as corresponding authors.
■ ACKNOWLEDGMENT
This research was supported in part by the intramural program
of the National Cancer Center, Center for Cancer Research,
National Institutes of Health (project Z1A BC 005270) and by
a grant from the National Research Foundation (NRF) of Korea
(NRF-2016M3A9B5939892).
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