6,6-Fused heterocyclic ureas as highly potent TRPV1 antagonists

Wei Sun; Hyo Shin Kim; Sunho Lee; Aeran Jung; Sung Eun Kim; Jihyae Ann; Suyoung Yoon; Sun Choi; Jin Hee Lee; Peter M. Blumberg; Robert Frank-Foltyn; Gregor Bahrenberg; Klaus Schiene; Hannelore Stockhausen; Thomas Christoph; Sven Frormann; Jeewoo Lee

doi:10.1016/j.bmcl.2014.12.086

6,6-Fused heterocyclic ureas as highly potent TRPV1 antagonists

Wei Sun, Hyo Shin Kim, Sunho Lee, Aeran Jung, Sung Eun Kim, Jihyae Ann, Suyoung Yoon, Sun Choi, Jin Hee Lee, Peter M. Blumberg, Robert Frank-Foltyn, Gregor Bahrenberg, Klaus Schiene, Hannelore Stockhausen, Thomas Christoph, Sven Frormann, Jeewoo Lee

Department of Pharmaceutical Sciences

Research output: Contribution to journal › Article › peer-review

5 Scopus citations

Abstract

A series of N-[{2-(4-methylpiperidin-1-yl)-6-(trifluoromethyl)-pyridin-3-yl}methyl] N′-(6,6-fused heterocyclic) ureas have been investigated as hTRPV1 antagonists. Among them, compound 15 showed highly potent TRPV1 antagonism to capsaicin, with K_i(ant) = 0.2 nM, as well as antagonism to other activators, and it was efficacious in a pain model. A docking study of 15 with our hTRPV1 homology model indicates that there is crucial hydrogen bonding between the ring nitrogen and the receptor, contributing to its potency.

Original language	English
Pages (from-to)	803-806
Number of pages	4
Journal	Bioorganic and Medicinal Chemistry Letters
Volume	25
Issue number	4
DOIs	https://doi.org/10.1016/j.bmcl.2014.12.086
State	Published - 15 Feb 2015

Bibliographical note

Funding Information:
This research was supported by Grants from Grunenthal , the Korea Health Technology R&D Project (HI13D2358), National Research Foundation of Korea ( R11-2007-107-02001-0 ), the National Leading Research Lab Program (2011-0028885), and in part by the Intramural Research Program of NIH, Center for Cancer Research, NCI (Project Z1A BC 005270).

Publisher Copyright:
© 2015 Elsevier Ltd. All rights reserved.

Keywords

Analgesic
Molecular modeling
TRPV1 antagonist
Vanilloid receptor 1

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10.1016/j.bmcl.2014.12.086

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Sun, W., Kim, H. S., Lee, S., Jung, A., Kim, S. E., Ann, J., Yoon, S., Choi, S., Lee, J. H., Blumberg, P. M., Frank-Foltyn, R., Bahrenberg, G., Schiene, K., Stockhausen, H., Christoph, T., Frormann, S., & Lee, J. (2015). 6,6-Fused heterocyclic ureas as highly potent TRPV1 antagonists. Bioorganic and Medicinal Chemistry Letters, 25(4), 803-806. https://doi.org/10.1016/j.bmcl.2014.12.086

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title = "6,6-Fused heterocyclic ureas as highly potent TRPV1 antagonists",

abstract = "A series of N-[{2-(4-methylpiperidin-1-yl)-6-(trifluoromethyl)-pyridin-3-yl}methyl] N′-(6,6-fused heterocyclic) ureas have been investigated as hTRPV1 antagonists. Among them, compound 15 showed highly potent TRPV1 antagonism to capsaicin, with Ki(ant) = 0.2 nM, as well as antagonism to other activators, and it was efficacious in a pain model. A docking study of 15 with our hTRPV1 homology model indicates that there is crucial hydrogen bonding between the ring nitrogen and the receptor, contributing to its potency.",

keywords = "Analgesic, Molecular modeling, TRPV1 antagonist, Vanilloid receptor 1",

author = "Wei Sun and Kim, {Hyo Shin} and Sunho Lee and Aeran Jung and Kim, {Sung Eun} and Jihyae Ann and Suyoung Yoon and Sun Choi and Lee, {Jin Hee} and Blumberg, {Peter M.} and Robert Frank-Foltyn and Gregor Bahrenberg and Klaus Schiene and Hannelore Stockhausen and Thomas Christoph and Sven Frormann and Jeewoo Lee",

note = "Funding Information: This research was supported by Grants from Grunenthal , the Korea Health Technology R&D Project (HI13D2358), National Research Foundation of Korea ( R11-2007-107-02001-0 ), the National Leading Research Lab Program (2011-0028885), and in part by the Intramural Research Program of NIH, Center for Cancer Research, NCI (Project Z1A BC 005270). Publisher Copyright: {\textcopyright} 2015 Elsevier Ltd. All rights reserved.",

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doi = "10.1016/j.bmcl.2014.12.086",

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Sun, W, Kim, HS, Lee, S, Jung, A, Kim, SE, Ann, J, Yoon, S, Choi, S, Lee, JH, Blumberg, PM, Frank-Foltyn, R, Bahrenberg, G, Schiene, K, Stockhausen, H, Christoph, T, Frormann, S & Lee, J 2015, '6,6-Fused heterocyclic ureas as highly potent TRPV1 antagonists', Bioorganic and Medicinal Chemistry Letters, vol. 25, no. 4, pp. 803-806. https://doi.org/10.1016/j.bmcl.2014.12.086

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AU - Kim, Hyo Shin

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AU - Kim, Sung Eun

AU - Ann, Jihyae

AU - Yoon, Suyoung

AU - Choi, Sun

AU - Lee, Jin Hee

AU - Blumberg, Peter M.

AU - Frank-Foltyn, Robert

AU - Bahrenberg, Gregor

AU - Schiene, Klaus

AU - Stockhausen, Hannelore

AU - Christoph, Thomas

AU - Frormann, Sven

AU - Lee, Jeewoo

N1 - Funding Information: This research was supported by Grants from Grunenthal , the Korea Health Technology R&D Project (HI13D2358), National Research Foundation of Korea ( R11-2007-107-02001-0 ), the National Leading Research Lab Program (2011-0028885), and in part by the Intramural Research Program of NIH, Center for Cancer Research, NCI (Project Z1A BC 005270). Publisher Copyright: © 2015 Elsevier Ltd. All rights reserved.

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N2 - A series of N-[{2-(4-methylpiperidin-1-yl)-6-(trifluoromethyl)-pyridin-3-yl}methyl] N′-(6,6-fused heterocyclic) ureas have been investigated as hTRPV1 antagonists. Among them, compound 15 showed highly potent TRPV1 antagonism to capsaicin, with Ki(ant) = 0.2 nM, as well as antagonism to other activators, and it was efficacious in a pain model. A docking study of 15 with our hTRPV1 homology model indicates that there is crucial hydrogen bonding between the ring nitrogen and the receptor, contributing to its potency.

AB - A series of N-[{2-(4-methylpiperidin-1-yl)-6-(trifluoromethyl)-pyridin-3-yl}methyl] N′-(6,6-fused heterocyclic) ureas have been investigated as hTRPV1 antagonists. Among them, compound 15 showed highly potent TRPV1 antagonism to capsaicin, with Ki(ant) = 0.2 nM, as well as antagonism to other activators, and it was efficacious in a pain model. A docking study of 15 with our hTRPV1 homology model indicates that there is crucial hydrogen bonding between the ring nitrogen and the receptor, contributing to its potency.

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ER -

6,6-Fused heterocyclic ureas as highly potent TRPV1 antagonists

Abstract

Bibliographical note

Keywords

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