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

Department of 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

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

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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

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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",

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

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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

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AU - Ann, Jihyae

AU - Jung, Aeran

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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

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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.

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JO - Bioorganic and Medicinal Chemistry

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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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