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

Hyungchul Ryu; Sejin Seo; Seong Hee Cho; Ho Shin Kim; Aeran Jung; Dong Wook Kang; Karam Son; Minghua Cui; Sun Hye Hong; Pankaz Kumar Sharma; Sun Choi; Peter M. Blumberg; Robert Frank-Foltyn; Gregor Bahrenberg; Hannelore Stockhausen; Klaus Schiene; Thomas Christoph; Sven Frormann; Jeewoo Lee

doi:10.1016/j.bmcl.2014.05.074

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

Hyungchul Ryu, Sejin Seo, Seong Hee Cho, Ho Shin Kim, Aeran Jung, Dong Wook Kang, Karam Son, Minghua Cui, Sun Hye Hong, Pankaz Kumar Sharma, Sun Choi, Peter M. Blumberg, Robert Frank-Foltyn, Gregor Bahrenberg, Hannelore Stockhausen, Klaus Schiene, 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-alkyl/alkenyl pyridine C-region derivatives of 2-(3-fluoro-4-methylsulfonylaminophenyl)propanamides were investigated as hTRPV1 antagonists. Multiple compounds showed excellent and stereospecific TRPV1 antagonism with better potency than previous lead 2. Among them, compound 15f demonstrated a strong analgesic profile in a rat neuropathic pain model and blocked capsaicin-induced hypothermia in a dose-dependent manner. Docking analysis of (S)-15f with our hTRPV1 homology model provided insight into its specific binding mode.

Original language	English
Pages (from-to)	4039-4043
Number of pages	5
Journal	Bioorganic and Medicinal Chemistry Letters
Volume	24
Issue number	16
DOIs	https://doi.org/10.1016/j.bmcl.2014.05.074
State	Published - 15 Aug 2014

Bibliographical note

Funding Information:
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, USA (Project Z1A BC 005270).

Keywords

Capsaicin
Molecular modeling
Resiniferatoxin
TRPV1 antagonist
Vanilloid receptor 1

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10.1016/j.bmcl.2014.05.074

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Ryu, H., Seo, S., Cho, S. H., Kim, H. S., Jung, A., Kang, D. W., Son, K., Cui, M., Hong, S. H., Sharma, P. K., Choi, S., Blumberg, P. M., Frank-Foltyn, R., Bahrenberg, G., Stockhausen, H., Schiene, K., Christoph, T., Frormann, S., & Lee, J. (2014). 2-Alkyl/alkenyl substituted pyridine C-region analogues of 2-(3-fluoro-4-methylsulfonylaminophenyl)propanamides as highly potent TRPV1 antagonists. Bioorganic and Medicinal Chemistry Letters, 24(16), 4039-4043. https://doi.org/10.1016/j.bmcl.2014.05.074

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

abstract = "A series of 2-alkyl/alkenyl pyridine C-region derivatives of 2-(3-fluoro-4-methylsulfonylaminophenyl)propanamides were investigated as hTRPV1 antagonists. Multiple compounds showed excellent and stereospecific TRPV1 antagonism with better potency than previous lead 2. Among them, compound 15f demonstrated a strong analgesic profile in a rat neuropathic pain model and blocked capsaicin-induced hypothermia in a dose-dependent manner. Docking analysis of (S)-15f 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 Cho, {Seong Hee} and Kim, {Ho Shin} and Aeran Jung and Kang, {Dong Wook} and Karam Son and Minghua Cui and Hong, {Sun Hye} and Sharma, {Pankaz Kumar} and Sun Choi and Blumberg, {Peter M.} and Robert Frank-Foltyn and Gregor Bahrenberg and Hannelore Stockhausen and Klaus Schiene and Thomas Christoph and Sven Frormann and Jeewoo Lee",

note = "Funding Information: 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, USA (Project Z1A BC 005270).",

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doi = "10.1016/j.bmcl.2014.05.074",

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Ryu, H, Seo, S, Cho, SH, Kim, HS, Jung, A, Kang, DW, Son, K, Cui, M, Hong, SH, Sharma, PK, Choi, S, Blumberg, PM, Frank-Foltyn, R, Bahrenberg, G, Stockhausen, H, Schiene, K, Christoph, T, Frormann, S & Lee, J 2014, '2-Alkyl/alkenyl 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. 4039-4043. https://doi.org/10.1016/j.bmcl.2014.05.074

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AU - Ryu, Hyungchul

AU - Seo, Sejin

AU - Cho, Seong Hee

AU - Kim, Ho Shin

AU - Jung, Aeran

AU - Kang, Dong Wook

AU - Son, Karam

AU - Cui, Minghua

AU - Hong, Sun Hye

AU - Sharma, Pankaz Kumar

AU - Choi, Sun

AU - Blumberg, Peter M.

AU - Frank-Foltyn, Robert

AU - Bahrenberg, Gregor

AU - Stockhausen, Hannelore

AU - Schiene, Klaus

AU - Christoph, Thomas

AU - Frormann, Sven

AU - Lee, Jeewoo

N1 - Funding Information: 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, USA (Project Z1A BC 005270).

PY - 2014/8/15

Y1 - 2014/8/15

N2 - A series of 2-alkyl/alkenyl pyridine C-region derivatives of 2-(3-fluoro-4-methylsulfonylaminophenyl)propanamides were investigated as hTRPV1 antagonists. Multiple compounds showed excellent and stereospecific TRPV1 antagonism with better potency than previous lead 2. Among them, compound 15f demonstrated a strong analgesic profile in a rat neuropathic pain model and blocked capsaicin-induced hypothermia in a dose-dependent manner. Docking analysis of (S)-15f with our hTRPV1 homology model provided insight into its specific binding mode.

AB - A series of 2-alkyl/alkenyl pyridine C-region derivatives of 2-(3-fluoro-4-methylsulfonylaminophenyl)propanamides were investigated as hTRPV1 antagonists. Multiple compounds showed excellent and stereospecific TRPV1 antagonism with better potency than previous lead 2. Among them, compound 15f demonstrated a strong analgesic profile in a rat neuropathic pain model and blocked capsaicin-induced hypothermia in a dose-dependent manner. Docking analysis of (S)-15f with our hTRPV1 homology model provided insight into its specific binding mode.

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KW - Molecular modeling

KW - Resiniferatoxin

KW - TRPV1 antagonist

KW - Vanilloid receptor 1

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AN - SCOPUS:84905914977

SN - 0960-894X

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SP - 4039

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JO - Bioorganic and Medicinal Chemistry Letters

JF - Bioorganic and Medicinal Chemistry Letters

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ER -

2-Alkyl/alkenyl 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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