TRPV1 antagonist with high analgesic efficacy: 2-Thio pyridine C-region analogues of 2-(3-fluoro-4-methylsulfonylaminophenyl)propanamides

Tae Hwan Ha; Hyungchul Ryu; Sung Eun Kim; Ho Shin Kim; Jihyae Ann; Phuong Thao Tran; Van Hai Hoang; Karam Son; Minghua Cui; Sun Choi; Peter M. Blumberg; Robert Frank; Gregor Bahrenberg; Klaus Schiene; Thomas Christoph; Sven Frormann; Jeewoo Lee

doi:10.1016/j.bmc.2013.08.015

TRPV1 antagonist with high analgesic efficacy: 2-Thio pyridine C-region analogues of 2-(3-fluoro-4-methylsulfonylaminophenyl)propanamides

Tae Hwan Ha, Hyungchul Ryu, Sung Eun Kim, Ho Shin Kim, Jihyae Ann, Phuong Thao Tran, Van Hai Hoang, Karam Son, Minghua Cui, Sun Choi, Peter M. Blumberg, Robert Frank, Gregor Bahrenberg, Klaus Schiene, Thomas Christoph, Sven Frormann, Jeewoo Lee

Department of Pharmaceutical Sciences

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

22 Scopus citations

Abstract

A series of 2-thio pyridine C-region analogues of 2-(3-fluoro-4- methylsulfonylaminophenyl)propanamides were investigated as hTRPV1 antagonists. Among them, compound 24S showed stereospecific and excellent TRPV1 antagonism of capsaicin-induced activation. Further, it demonstrated strong anti-allodynic in a rat neuropathic pain model. Consistent with its action in vitro being through TRPV1, compound 24S blocked capsaicin-induced hypothermia in mice. Docking analysis of 24S with our hTRPV1 homology model was performed to identify its binding mode.

Original language	English
Pages (from-to)	6657-6664
Number of pages	8
Journal	Bioorganic and Medicinal Chemistry
Volume	21
Issue number	21
DOIs	https://doi.org/10.1016/j.bmc.2013.08.015
State	Published - 1 Nov 2013

Bibliographical note

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

Keywords

Analgesic
Capsaicin
Resiniferatoxin
TRPV1 antagonists

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10.1016/j.bmc.2013.08.015

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Ha, T. H., Ryu, H., Kim, S. E., Kim, H. S., Ann, J., Tran, P. T., Hoang, V. H., Son, K., Cui, M., Choi, S., Blumberg, P. M., Frank, R., Bahrenberg, G., Schiene, K., Christoph, T., Frormann, S., & Lee, J. (2013). TRPV1 antagonist with high analgesic efficacy: 2-Thio pyridine C-region analogues of 2-(3-fluoro-4-methylsulfonylaminophenyl)propanamides. Bioorganic and Medicinal Chemistry, 21(21), 6657-6664. https://doi.org/10.1016/j.bmc.2013.08.015

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title = "TRPV1 antagonist with high analgesic efficacy: 2-Thio pyridine C-region analogues of 2-(3-fluoro-4-methylsulfonylaminophenyl)propanamides",

abstract = "A series of 2-thio pyridine C-region analogues of 2-(3-fluoro-4- methylsulfonylaminophenyl)propanamides were investigated as hTRPV1 antagonists. Among them, compound 24S showed stereospecific and excellent TRPV1 antagonism of capsaicin-induced activation. Further, it demonstrated strong anti-allodynic in a rat neuropathic pain model. Consistent with its action in vitro being through TRPV1, compound 24S blocked capsaicin-induced hypothermia in mice. Docking analysis of 24S with our hTRPV1 homology model was performed to identify its binding mode.",

keywords = "Analgesic, Capsaicin, Resiniferatoxin, TRPV1 antagonists",

author = "Ha, {Tae Hwan} and Hyungchul Ryu and Kim, {Sung Eun} and Kim, {Ho Shin} and Jihyae Ann and Tran, {Phuong Thao} and Hoang, {Van Hai} and Karam Son and Minghua Cui and Sun Choi and Blumberg, {Peter M.} and Robert Frank and Gregor Bahrenberg and Klaus Schiene and Thomas Christoph and Sven Frormann and Jeewoo Lee",

note = "Funding Information: This research was supported by Research Grants from Grunenthal, Grants from the National Research Foundation of Korea (NRF) ( R11-2007-107-02001-0 ), Grants from the National Leading Research Lab (NLRL) program ( 2011-0028885 ), and in part by the Intramural Research Program of NIH, Center for Cancer Research, NCI (Project Z1A BC 005270 ).",

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doi = "10.1016/j.bmc.2013.08.015",

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Ha, TH, Ryu, H, Kim, SE, Kim, HS, Ann, J, Tran, PT, Hoang, VH, Son, K, Cui, M, Choi, S, Blumberg, PM, Frank, R, Bahrenberg, G, Schiene, K, Christoph, T, Frormann, S & Lee, J 2013, 'TRPV1 antagonist with high analgesic efficacy: 2-Thio pyridine C-region analogues of 2-(3-fluoro-4-methylsulfonylaminophenyl)propanamides', Bioorganic and Medicinal Chemistry, vol. 21, no. 21, pp. 6657-6664. https://doi.org/10.1016/j.bmc.2013.08.015

TY - JOUR

T1 - TRPV1 antagonist with high analgesic efficacy

T2 - 2-Thio pyridine C-region analogues of 2-(3-fluoro-4-methylsulfonylaminophenyl)propanamides

AU - Ha, Tae Hwan

AU - Ryu, Hyungchul

AU - Kim, Sung Eun

AU - Kim, Ho Shin

AU - Ann, Jihyae

AU - Tran, Phuong Thao

AU - Hoang, Van Hai

AU - Son, Karam

AU - Cui, Minghua

AU - Choi, Sun

AU - Blumberg, Peter M.

AU - Frank, Robert

AU - Bahrenberg, Gregor

AU - Schiene, Klaus

AU - Christoph, Thomas

AU - Frormann, Sven

AU - Lee, Jeewoo

N1 - Funding Information: This research was supported by Research Grants from Grunenthal, Grants from the National Research Foundation of Korea (NRF) ( R11-2007-107-02001-0 ), Grants from the National Leading Research Lab (NLRL) program ( 2011-0028885 ), and in part by the Intramural Research Program of NIH, Center for Cancer Research, NCI (Project Z1A BC 005270 ).

PY - 2013/11/1

Y1 - 2013/11/1

N2 - A series of 2-thio pyridine C-region analogues of 2-(3-fluoro-4- methylsulfonylaminophenyl)propanamides were investigated as hTRPV1 antagonists. Among them, compound 24S showed stereospecific and excellent TRPV1 antagonism of capsaicin-induced activation. Further, it demonstrated strong anti-allodynic in a rat neuropathic pain model. Consistent with its action in vitro being through TRPV1, compound 24S blocked capsaicin-induced hypothermia in mice. Docking analysis of 24S with our hTRPV1 homology model was performed to identify its binding mode.

AB - A series of 2-thio pyridine C-region analogues of 2-(3-fluoro-4- methylsulfonylaminophenyl)propanamides were investigated as hTRPV1 antagonists. Among them, compound 24S showed stereospecific and excellent TRPV1 antagonism of capsaicin-induced activation. Further, it demonstrated strong anti-allodynic in a rat neuropathic pain model. Consistent with its action in vitro being through TRPV1, compound 24S blocked capsaicin-induced hypothermia in mice. Docking analysis of 24S with our hTRPV1 homology model was performed to identify its binding mode.

KW - Analgesic

KW - Capsaicin

KW - Resiniferatoxin

KW - TRPV1 antagonists

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SN - 0968-0896

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EP - 6664

JO - Bioorganic and Medicinal Chemistry

JF - Bioorganic and Medicinal Chemistry

IS - 21

ER -

TRPV1 antagonist with high analgesic efficacy: 2-Thio pyridine C-region analogues of 2-(3-fluoro-4-methylsulfonylaminophenyl)propanamides

Abstract

Bibliographical note

Keywords

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