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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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

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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.

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KW - TRPV1 antagonist

KW - Vanilloid receptor 1

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AN - SCOPUS:84905914977

SN - 0960-894X

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SP - 4039

EP - 4043

JO - Bioorganic and Medicinal Chemistry Letters

JF - Bioorganic and Medicinal Chemistry Letters

IS - 16

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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