t-Butyl pyridine and phenyl C-region analogues of 2-(3-fluoro-4-methylsulfonylaminophenyl)propanamides as potent TRPV1 antagonists

Sunho Lee; Dong Wook Kang; Hyung Chul Ryu; Changhoon Kim; Jihyae Ann; Hobin Lee; Eunhye Kim; Sunhye Hong; Sun Choi; Peter M. Blumberg; Robert Frank-Foltyn; Gregor Bahrenberg; Hannelore Stockhausen; Thomas Christoph; Jeewoo Lee

doi:10.1016/j.bmc.2017.03.004

t-Butyl pyridine and phenyl C-region analogues of 2-(3-fluoro-4-methylsulfonylaminophenyl)propanamides as potent TRPV1 antagonists

Sunho Lee, Dong Wook Kang, Hyung Chul Ryu, Changhoon Kim, Jihyae Ann, Hobin Lee, Eunhye Kim, Sunhye Hong, Sun Choi, Peter M. Blumberg, Robert Frank-Foltyn, Gregor Bahrenberg, Hannelore Stockhausen, Thomas Christoph, Jeewoo Lee

Department of Pharmaceutical Sciences

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

8 Scopus citations

Abstract

A series of 2-substituted 6-t-butylpyridine and 4-t-butylphenyl C-region analogues of 2-(3-fluoro-4-methylsulfonamidophenyl)propanamides were investigated for hTRPV1 antagonism. The analysis of structure activity relationships indicated that the pyridine derivatives generally exhibited a little better antagonism than did the corresponding phenyl surrogates for most of the series. Among the compounds, compound 7 showed excellent antagonism toward capsaicin activation with K_i = 0.1 nM and compound 60S demonstrated a strong antiallodynic effect with 83% MPE at 10 mg/kg in the neuropathic pain model. The docking study of 7S in our hTRPV1 homology model indicated that the interactions between the A/B-regions of 7S with Tyr511 and the interactions between the t-butyl and ethyl groups in the C-region of 7S with the two hydrophobic binding pockets of hTRPV1 contributed to the high potency.

Original language	English
Pages (from-to)	2451-2462
Number of pages	12
Journal	Bioorganic and Medicinal Chemistry
Volume	25
Issue number	8
DOIs	https://doi.org/10.1016/j.bmc.2017.03.004
State	Published - 2017

Bibliographical note

Funding Information:
This research was supported by research grants from Grünenthal in Germany, a grant from the National Research Foundation (NRF) of Korea (NRF-2016M3A9B5939892), a grant from the National Leading Research Lab (NLRL) program (2011-0028885) funded by the Ministry of Science, ICT and Future Planning (MSIP) and the NRF, and in part by the Intramural Research Program of the National Institutes of Health, Center for Cancer Research, National Cancer Institute (Project Z1A BC 005270) in the USA.

Publisher Copyright:
© 2017 Elsevier Ltd

Keywords

Analgesic
TRPV1 antagonists
Vanilloid receptor 1

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10.1016/j.bmc.2017.03.004

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Lee, S., Kang, D. W., Ryu, H. C., Kim, C., Ann, J., Lee, H., Kim, E., Hong, S., Choi, S., Blumberg, P. M., Frank-Foltyn, R., Bahrenberg, G., Stockhausen, H., Christoph, T., & Lee, J. (2017). t-Butyl pyridine and phenyl C-region analogues of 2-(3-fluoro-4-methylsulfonylaminophenyl)propanamides as potent TRPV1 antagonists. Bioorganic and Medicinal Chemistry, 25(8), 2451-2462. https://doi.org/10.1016/j.bmc.2017.03.004

@article{c6c70dc427ee412bac658d772fa6acd3,

title = "t-Butyl pyridine and phenyl C-region analogues of 2-(3-fluoro-4-methylsulfonylaminophenyl)propanamides as potent TRPV1 antagonists",

abstract = "A series of 2-substituted 6-t-butylpyridine and 4-t-butylphenyl C-region analogues of 2-(3-fluoro-4-methylsulfonamidophenyl)propanamides were investigated for hTRPV1 antagonism. The analysis of structure activity relationships indicated that the pyridine derivatives generally exhibited a little better antagonism than did the corresponding phenyl surrogates for most of the series. Among the compounds, compound 7 showed excellent antagonism toward capsaicin activation with Ki = 0.1 nM and compound 60S demonstrated a strong antiallodynic effect with 83% MPE at 10 mg/kg in the neuropathic pain model. The docking study of 7S in our hTRPV1 homology model indicated that the interactions between the A/B-regions of 7S with Tyr511 and the interactions between the t-butyl and ethyl groups in the C-region of 7S with the two hydrophobic binding pockets of hTRPV1 contributed to the high potency.",

keywords = "Analgesic, TRPV1 antagonists, Vanilloid receptor 1",

author = "Sunho Lee and Kang, {Dong Wook} and Ryu, {Hyung Chul} and Changhoon Kim and Jihyae Ann and Hobin Lee and Eunhye Kim and Sunhye Hong and Sun Choi and Blumberg, {Peter M.} and Robert Frank-Foltyn and Gregor Bahrenberg and Hannelore Stockhausen and Thomas Christoph and Jeewoo Lee",

note = "Funding Information: This research was supported by research grants from Gr{\"u}nenthal in Germany, a grant from the National Research Foundation (NRF) of Korea (NRF-2016M3A9B5939892), a grant from the National Leading Research Lab (NLRL) program (2011-0028885) funded by the Ministry of Science, ICT and Future Planning (MSIP) and the NRF, and in part by the Intramural Research Program of the National Institutes of Health, Center for Cancer Research, National Cancer Institute (Project Z1A BC 005270) in the USA. Publisher Copyright: {\textcopyright} 2017 Elsevier Ltd",

year = "2017",

doi = "10.1016/j.bmc.2017.03.004",

language = "English",

volume = "25",

pages = "2451--2462",

journal = "Bioorganic and Medicinal Chemistry",

issn = "0968-0896",

publisher = "Elsevier Ltd.",

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Lee, S, Kang, DW, Ryu, HC, Kim, C, Ann, J, Lee, H, Kim, E, Hong, S, Choi, S, Blumberg, PM, Frank-Foltyn, R, Bahrenberg, G, Stockhausen, H, Christoph, T & Lee, J 2017, 't-Butyl pyridine and phenyl C-region analogues of 2-(3-fluoro-4-methylsulfonylaminophenyl)propanamides as potent TRPV1 antagonists', Bioorganic and Medicinal Chemistry, vol. 25, no. 8, pp. 2451-2462. https://doi.org/10.1016/j.bmc.2017.03.004

TY - JOUR

T1 - t-Butyl pyridine and phenyl C-region analogues of 2-(3-fluoro-4-methylsulfonylaminophenyl)propanamides as potent TRPV1 antagonists

AU - Lee, Sunho

AU - Kang, Dong Wook

AU - Ryu, Hyung Chul

AU - Kim, Changhoon

AU - Ann, Jihyae

AU - Lee, Hobin

AU - Kim, Eunhye

AU - Hong, Sunhye

AU - Choi, Sun

AU - Blumberg, Peter M.

AU - Frank-Foltyn, Robert

AU - Bahrenberg, Gregor

AU - Stockhausen, Hannelore

AU - Christoph, Thomas

AU - Lee, Jeewoo

N1 - Funding Information: This research was supported by research grants from Grünenthal in Germany, a grant from the National Research Foundation (NRF) of Korea (NRF-2016M3A9B5939892), a grant from the National Leading Research Lab (NLRL) program (2011-0028885) funded by the Ministry of Science, ICT and Future Planning (MSIP) and the NRF, and in part by the Intramural Research Program of the National Institutes of Health, Center for Cancer Research, National Cancer Institute (Project Z1A BC 005270) in the USA. Publisher Copyright: © 2017 Elsevier Ltd

PY - 2017

Y1 - 2017

N2 - A series of 2-substituted 6-t-butylpyridine and 4-t-butylphenyl C-region analogues of 2-(3-fluoro-4-methylsulfonamidophenyl)propanamides were investigated for hTRPV1 antagonism. The analysis of structure activity relationships indicated that the pyridine derivatives generally exhibited a little better antagonism than did the corresponding phenyl surrogates for most of the series. Among the compounds, compound 7 showed excellent antagonism toward capsaicin activation with Ki = 0.1 nM and compound 60S demonstrated a strong antiallodynic effect with 83% MPE at 10 mg/kg in the neuropathic pain model. The docking study of 7S in our hTRPV1 homology model indicated that the interactions between the A/B-regions of 7S with Tyr511 and the interactions between the t-butyl and ethyl groups in the C-region of 7S with the two hydrophobic binding pockets of hTRPV1 contributed to the high potency.

AB - A series of 2-substituted 6-t-butylpyridine and 4-t-butylphenyl C-region analogues of 2-(3-fluoro-4-methylsulfonamidophenyl)propanamides were investigated for hTRPV1 antagonism. The analysis of structure activity relationships indicated that the pyridine derivatives generally exhibited a little better antagonism than did the corresponding phenyl surrogates for most of the series. Among the compounds, compound 7 showed excellent antagonism toward capsaicin activation with Ki = 0.1 nM and compound 60S demonstrated a strong antiallodynic effect with 83% MPE at 10 mg/kg in the neuropathic pain model. The docking study of 7S in our hTRPV1 homology model indicated that the interactions between the A/B-regions of 7S with Tyr511 and the interactions between the t-butyl and ethyl groups in the C-region of 7S with the two hydrophobic binding pockets of hTRPV1 contributed to the high potency.

KW - Analgesic

KW - TRPV1 antagonists

KW - Vanilloid receptor 1

UR - http://www.scopus.com/inward/record.url?scp=85016300126&partnerID=8YFLogxK

U2 - 10.1016/j.bmc.2017.03.004

DO - 10.1016/j.bmc.2017.03.004

M3 - Article

C2 - 28314510

AN - SCOPUS:85016300126

SN - 0968-0896

VL - 25

SP - 2451

EP - 2462

JO - Bioorganic and Medicinal Chemistry

JF - Bioorganic and Medicinal Chemistry

IS - 8

ER -

t-Butyl pyridine and phenyl C-region analogues of 2-(3-fluoro-4-methylsulfonylaminophenyl)propanamides as potent TRPV1 antagonists

Abstract

Bibliographical note

Keywords

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