2-Aryl substituted pyridine C-region analogues of 2-(3-fluoro-4- methylsulfonylaminophenyl)propanamides as highly potent TRPV1 antagonists

Hyungchul Ryu; Sejin Seo; Myeong Seop Kim; Mi Yeon Kim; Ho Shin Kim; Jihyae Ann; Phuong Thao Tran; Van Hai Hoang; Jieun Byun; Minghua Cui; Karam Son; Pankaz Kumar Sharma; Sun Choi; Peter M. Blumberg; Robert Frank-Foltyn; Gregor Bahrenberg; Babette Yvonne Koegel; Thomas Christoph; Sven Frormann; Jeewoo Lee

doi:10.1016/j.bmcl.2014.05.072

2-Aryl substituted pyridine C-region analogues of 2-(3-fluoro-4- methylsulfonylaminophenyl)propanamides as highly potent TRPV1 antagonists

Hyungchul Ryu, Sejin Seo, Myeong Seop Kim, Mi Yeon Kim, Ho Shin Kim, Jihyae Ann, Phuong Thao Tran, Van Hai Hoang, Jieun Byun, Minghua Cui, Karam Son, Pankaz Kumar Sharma, Sun Choi, Peter M. Blumberg, Robert Frank-Foltyn, Gregor Bahrenberg, Babette Yvonne Koegel, Thomas Christoph, Sven Frormann, Jeewoo Lee

Department of Pharmaceutical Sciences

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

15 Scopus citations

Abstract

A series of 2-aryl pyridine C-region derivatives of 2-(3-fluoro-4- methylsulfonylaminophenyl)propanamides were investigated as hTRPV1 antagonists. Multiple compounds showed highly potent TRPV1 antagonism toward capsaicin comparable to previous lead 7. Among them, compound 9 demonstrated anti-allodynia in a mouse neuropathic pain model and blocked capsaicin-induced hypothermia in a dose-dependent manner. Docking analysis of 9 with our hTRPV1 homology model provided insight into its specific binding mode.

Original language	English
Pages (from-to)	4044-4047
Number of pages	4
Journal	Bioorganic and Medicinal Chemistry Letters
Volume	24
Issue number	16
DOIs	https://doi.org/10.1016/j.bmcl.2014.05.072
State	Published - 15 Aug 2014

Bibliographical note

Funding Information:
We greatly acknowledge Elke Schumacher and Franz-Josef Butz for technical assistance in CCI and Cap hypothermia studies, resp. This research was supported by Research Grants from Grunenthal , Germany, 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), Republic of Korea, and in part by the Intramural Research Program of NIH, Center for Cancer Research, NCI (Project Z1A BC 005270), USA.

Keywords

Capsaicin
Molecular modeling
Resiniferatoxin
TRPV1 antagonist
Vanilloid receptor 1

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10.1016/j.bmcl.2014.05.072

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Ryu, H., Seo, S., Kim, M. S., Kim, M. Y., Kim, H. S., Ann, J., Tran, P. T., Hoang, V. H., Byun, J., Cui, M., Son, K., Sharma, P. K., Choi, S., Blumberg, P. M., Frank-Foltyn, R., Bahrenberg, G., Koegel, B. Y., Christoph, T., Frormann, S., & Lee, J. (2014). 2-Aryl substituted pyridine C-region analogues of 2-(3-fluoro-4- methylsulfonylaminophenyl)propanamides as highly potent TRPV1 antagonists. Bioorganic and Medicinal Chemistry Letters, 24(16), 4044-4047. https://doi.org/10.1016/j.bmcl.2014.05.072

@article{f34579db5a1747c8a8afe47308a7a117,

title = "2-Aryl substituted pyridine C-region analogues of 2-(3-fluoro-4- methylsulfonylaminophenyl)propanamides as highly potent TRPV1 antagonists",

abstract = "A series of 2-aryl pyridine C-region derivatives of 2-(3-fluoro-4- methylsulfonylaminophenyl)propanamides were investigated as hTRPV1 antagonists. Multiple compounds showed highly potent TRPV1 antagonism toward capsaicin comparable to previous lead 7. Among them, compound 9 demonstrated anti-allodynia in a mouse neuropathic pain model and blocked capsaicin-induced hypothermia in a dose-dependent manner. Docking analysis of 9 with our hTRPV1 homology model provided insight into its specific binding mode.",

keywords = "Capsaicin, Molecular modeling, Resiniferatoxin, TRPV1 antagonist, Vanilloid receptor 1",

author = "Hyungchul Ryu and Sejin Seo and Kim, {Myeong Seop} and Kim, {Mi Yeon} and Kim, {Ho Shin} and Jihyae Ann and Tran, {Phuong Thao} and Hoang, {Van Hai} and Jieun Byun and Minghua Cui and Karam Son and Sharma, {Pankaz Kumar} and Sun Choi and Blumberg, {Peter M.} and Robert Frank-Foltyn and Gregor Bahrenberg and Koegel, {Babette Yvonne} and Thomas Christoph and Sven Frormann and Jeewoo Lee",

note = "Funding Information: We greatly acknowledge Elke Schumacher and Franz-Josef Butz for technical assistance in CCI and Cap hypothermia studies, resp. This research was supported by Research Grants from Grunenthal , Germany, 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), Republic of Korea, and in part by the Intramural Research Program of NIH, Center for Cancer Research, NCI (Project Z1A BC 005270), USA. ",

year = "2014",

month = aug,

day = "15",

doi = "10.1016/j.bmcl.2014.05.072",

language = "English",

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Ryu, H, Seo, S, Kim, MS, Kim, MY, Kim, HS, Ann, J, Tran, PT, Hoang, VH, Byun, J, Cui, M, Son, K, Sharma, PK, Choi, S, Blumberg, PM, Frank-Foltyn, R, Bahrenberg, G, Koegel, BY, Christoph, T, Frormann, S & Lee, J 2014, '2-Aryl substituted pyridine C-region analogues of 2-(3-fluoro-4- methylsulfonylaminophenyl)propanamides as highly potent TRPV1 antagonists', Bioorganic and Medicinal Chemistry Letters, vol. 24, no. 16, pp. 4044-4047. https://doi.org/10.1016/j.bmcl.2014.05.072

TY - JOUR

T1 - 2-Aryl substituted pyridine C-region analogues of 2-(3-fluoro-4- methylsulfonylaminophenyl)propanamides as highly potent TRPV1 antagonists

AU - Ryu, Hyungchul

AU - Seo, Sejin

AU - Kim, Myeong Seop

AU - Kim, Mi Yeon

AU - Kim, Ho Shin

AU - Ann, Jihyae

AU - Tran, Phuong Thao

AU - Hoang, Van Hai

AU - Byun, Jieun

AU - Cui, Minghua

AU - Son, Karam

AU - Sharma, Pankaz Kumar

AU - Choi, Sun

AU - Blumberg, Peter M.

AU - Frank-Foltyn, Robert

AU - Bahrenberg, Gregor

AU - Koegel, Babette Yvonne

AU - Christoph, Thomas

AU - Frormann, Sven

AU - Lee, Jeewoo

N1 - Funding Information: We greatly acknowledge Elke Schumacher and Franz-Josef Butz for technical assistance in CCI and Cap hypothermia studies, resp. This research was supported by Research Grants from Grunenthal , Germany, 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), Republic of Korea, and in part by the Intramural Research Program of NIH, Center for Cancer Research, NCI (Project Z1A BC 005270), USA.

PY - 2014/8/15

Y1 - 2014/8/15

N2 - A series of 2-aryl pyridine C-region derivatives of 2-(3-fluoro-4- methylsulfonylaminophenyl)propanamides were investigated as hTRPV1 antagonists. Multiple compounds showed highly potent TRPV1 antagonism toward capsaicin comparable to previous lead 7. Among them, compound 9 demonstrated anti-allodynia in a mouse neuropathic pain model and blocked capsaicin-induced hypothermia in a dose-dependent manner. Docking analysis of 9 with our hTRPV1 homology model provided insight into its specific binding mode.

AB - A series of 2-aryl pyridine C-region derivatives of 2-(3-fluoro-4- methylsulfonylaminophenyl)propanamides were investigated as hTRPV1 antagonists. Multiple compounds showed highly potent TRPV1 antagonism toward capsaicin comparable to previous lead 7. Among them, compound 9 demonstrated anti-allodynia in a mouse neuropathic pain model and blocked capsaicin-induced hypothermia in a dose-dependent manner. Docking analysis of 9 with our hTRPV1 homology model provided insight into its specific binding mode.

KW - Capsaicin

KW - Molecular modeling

KW - Resiniferatoxin

KW - TRPV1 antagonist

KW - Vanilloid receptor 1

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U2 - 10.1016/j.bmcl.2014.05.072

DO - 10.1016/j.bmcl.2014.05.072

M3 - Article

C2 - 25011915

AN - SCOPUS:84906101686

SN - 0960-894X

VL - 24

SP - 4044

EP - 4047

JO - Bioorganic and Medicinal Chemistry Letters

JF - Bioorganic and Medicinal Chemistry Letters

IS - 16

ER -

2-Aryl substituted pyridine C-region analogues of 2-(3-fluoro-4- methylsulfonylaminophenyl)propanamides as highly potent TRPV1 antagonists

Abstract

Bibliographical note

Keywords

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