Structure activity relationships of benzyl C-region analogs of 2-(3-fluoro-4-methylsulfonamidophenyl)propanamides as potent TRPV1 antagonists

Jihyae Ann; Aeran Jung; Mi Yeon Kim; Hyuk Min Kim; Hyungchul Ryu; Sunjoo Kim; Dong Wook Kang; Sunhye Hong; Minghua Cui; Sun Choi; Peter M. Blumberg; Robert Frank-Foltyn; Gregor Bahrenberg; Hannelore Stockhausen; Thomas Christoph; Jeewoo Lee

doi:10.1016/j.bmc.2015.10.001

Structure activity relationships of benzyl C-region analogs of 2-(3-fluoro-4-methylsulfonamidophenyl)propanamides as potent TRPV1 antagonists

Jihyae Ann, Aeran Jung, Mi Yeon Kim, Hyuk Min Kim, Hyungchul Ryu, Sunjoo Kim, Dong Wook Kang, Sunhye Hong, Minghua Cui, Sun Choi, Peter M. Blumberg, Robert Frank-Foltyn, Gregor Bahrenberg, Hannelore Stockhausen, Thomas Christoph, Jeewoo Lee

Pharmaceutical Sciences

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

7 Scopus citations

Abstract

A series of 2-substituted 4-(trifluoromethyl)benzyl C-region analogs of 2-(3-fluoro-4-methylsulfonamidophenyl)propanamides were investigated for hTRPV1 antagonism. The analysis indicated that the phenyl C-region derivatives exhibited better antagonism than those of the corresponding pyridine surrogates for most of the series examined. Among the phenyl C-region derivatives, the two best compounds 43 and 44S antagonized capsaicin selectively relative to their antagonism of other activators and showed excellent potencies with K_i(CAP) = 0.3 nM. These two compounds blocked capsaicin-induced hypothermia, consistent with TRPV1 as their site of action, and they demonstrated promising analgesic activities in a neuropathic pain model without hyperthermia. The docking study of 44S in our hTRPV1 homology model indicated that its binding mode was similar with that of its pyridine surrogate in the A- and B-regions but displayed a flipped configuration in the C-region.

Original language	English
Pages (from-to)	6844-6854
Number of pages	11
Journal	Bioorganic and Medicinal Chemistry
Volume	23
Issue number	21
DOIs	https://doi.org/10.1016/j.bmc.2015.10.001
State	Published - 1 Nov 2015

Bibliographical note

Funding Information:
This research was supported by research Grants from Grünenthal in Germany, grants from the Korea Science and Engineering Foundation (KOSEF) ( NRF-2007-0057057 ) and the National Leading Research Lab (NLRL) program ( 2011-0028885 ) in South Korea, and in part by the Intramural Research Program of the NIH , Center for Cancer Research, NCI (Project Z1A BC 005270) in the USA.

Publisher Copyright:
© 2015 Elsevier Ltd. All rights reserved.

Keywords

Analgesic
TRPV1 antagonists
Vanilloid receptor 1

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10.1016/j.bmc.2015.10.001

Cite this

Ann, J., Jung, A., Kim, M. Y., Kim, H. M., Ryu, H., Kim, S., Kang, D. W., Hong, S., Cui, M., Choi, S., Blumberg, P. M., Frank-Foltyn, R., Bahrenberg, G., Stockhausen, H., Christoph, T., & Lee, J. (2015). Structure activity relationships of benzyl C-region analogs of 2-(3-fluoro-4-methylsulfonamidophenyl)propanamides as potent TRPV1 antagonists. Bioorganic and Medicinal Chemistry, 23(21), 6844-6854. https://doi.org/10.1016/j.bmc.2015.10.001

@article{eb72467fac6f49949798d340be5d7bc6,

title = "Structure activity relationships of benzyl C-region analogs of 2-(3-fluoro-4-methylsulfonamidophenyl)propanamides as potent TRPV1 antagonists",

abstract = "A series of 2-substituted 4-(trifluoromethyl)benzyl C-region analogs of 2-(3-fluoro-4-methylsulfonamidophenyl)propanamides were investigated for hTRPV1 antagonism. The analysis indicated that the phenyl C-region derivatives exhibited better antagonism than those of the corresponding pyridine surrogates for most of the series examined. Among the phenyl C-region derivatives, the two best compounds 43 and 44S antagonized capsaicin selectively relative to their antagonism of other activators and showed excellent potencies with Ki(CAP) = 0.3 nM. These two compounds blocked capsaicin-induced hypothermia, consistent with TRPV1 as their site of action, and they demonstrated promising analgesic activities in a neuropathic pain model without hyperthermia. The docking study of 44S in our hTRPV1 homology model indicated that its binding mode was similar with that of its pyridine surrogate in the A- and B-regions but displayed a flipped configuration in the C-region.",

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

author = "Jihyae Ann and Aeran Jung and Kim, {Mi Yeon} and Kim, {Hyuk Min} and Hyungchul Ryu and Sunjoo Kim and Kang, {Dong Wook} and Sunhye Hong and Minghua Cui 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, grants from the Korea Science and Engineering Foundation (KOSEF) ( NRF-2007-0057057 ) and the National Leading Research Lab (NLRL) program ( 2011-0028885 ) in South Korea, and in part by the Intramural Research Program of the NIH , Center for Cancer Research, NCI (Project Z1A BC 005270) in the USA. Publisher Copyright: {\textcopyright} 2015 Elsevier Ltd. All rights reserved.",

year = "2015",

month = nov,

day = "1",

doi = "10.1016/j.bmc.2015.10.001",

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volume = "23",

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Ann, J, Jung, A, Kim, MY, Kim, HM, Ryu, H, Kim, S, Kang, DW, Hong, S, Cui, M, Choi, S, Blumberg, PM, Frank-Foltyn, R, Bahrenberg, G, Stockhausen, H, Christoph, T & Lee, J 2015, 'Structure activity relationships of benzyl C-region analogs of 2-(3-fluoro-4-methylsulfonamidophenyl)propanamides as potent TRPV1 antagonists', Bioorganic and Medicinal Chemistry, vol. 23, no. 21, pp. 6844-6854. https://doi.org/10.1016/j.bmc.2015.10.001

TY - JOUR

T1 - Structure activity relationships of benzyl C-region analogs of 2-(3-fluoro-4-methylsulfonamidophenyl)propanamides as potent TRPV1 antagonists

AU - Ann, Jihyae

AU - Jung, Aeran

AU - Kim, Mi Yeon

AU - Kim, Hyuk Min

AU - Ryu, Hyungchul

AU - Kim, Sunjoo

AU - Kang, Dong Wook

AU - Hong, Sunhye

AU - Cui, Minghua

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, grants from the Korea Science and Engineering Foundation (KOSEF) ( NRF-2007-0057057 ) and the National Leading Research Lab (NLRL) program ( 2011-0028885 ) in South Korea, and in part by the Intramural Research Program of the NIH , Center for Cancer Research, NCI (Project Z1A BC 005270) in the USA. Publisher Copyright: © 2015 Elsevier Ltd. All rights reserved.

PY - 2015/11/1

Y1 - 2015/11/1

N2 - A series of 2-substituted 4-(trifluoromethyl)benzyl C-region analogs of 2-(3-fluoro-4-methylsulfonamidophenyl)propanamides were investigated for hTRPV1 antagonism. The analysis indicated that the phenyl C-region derivatives exhibited better antagonism than those of the corresponding pyridine surrogates for most of the series examined. Among the phenyl C-region derivatives, the two best compounds 43 and 44S antagonized capsaicin selectively relative to their antagonism of other activators and showed excellent potencies with Ki(CAP) = 0.3 nM. These two compounds blocked capsaicin-induced hypothermia, consistent with TRPV1 as their site of action, and they demonstrated promising analgesic activities in a neuropathic pain model without hyperthermia. The docking study of 44S in our hTRPV1 homology model indicated that its binding mode was similar with that of its pyridine surrogate in the A- and B-regions but displayed a flipped configuration in the C-region.

AB - A series of 2-substituted 4-(trifluoromethyl)benzyl C-region analogs of 2-(3-fluoro-4-methylsulfonamidophenyl)propanamides were investigated for hTRPV1 antagonism. The analysis indicated that the phenyl C-region derivatives exhibited better antagonism than those of the corresponding pyridine surrogates for most of the series examined. Among the phenyl C-region derivatives, the two best compounds 43 and 44S antagonized capsaicin selectively relative to their antagonism of other activators and showed excellent potencies with Ki(CAP) = 0.3 nM. These two compounds blocked capsaicin-induced hypothermia, consistent with TRPV1 as their site of action, and they demonstrated promising analgesic activities in a neuropathic pain model without hyperthermia. The docking study of 44S in our hTRPV1 homology model indicated that its binding mode was similar with that of its pyridine surrogate in the A- and B-regions but displayed a flipped configuration in the C-region.

KW - Analgesic

KW - TRPV1 antagonists

KW - Vanilloid receptor 1

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DO - 10.1016/j.bmc.2015.10.001

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SN - 0968-0896

VL - 23

SP - 6844

EP - 6854

JO - Bioorganic and Medicinal Chemistry

JF - Bioorganic and Medicinal Chemistry

IS - 21

ER -

Structure activity relationships of benzyl C-region analogs of 2-(3-fluoro-4-methylsulfonamidophenyl)propanamides as potent TRPV1 antagonists

Abstract

Bibliographical note

Keywords

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