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",

language = "English",

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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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AN - SCOPUS:84885180625

SN - 0968-0896

VL - 21

SP - 6657

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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