2-(Halogenated Phenyl) acetamides and propanamides as potent TRPV1 antagonists

Jin Mi Kang; Sun Ok Kwon; Jihyae Ann; Sunho Lee; Changhoon Kim; Nayeon Do; Jin Ju Jeong; Peter M. Blumberg; Heejin Ha; Thi Ngoc Lan Vu; Sanghee Yoon; Sun Choi; Robert Frank-Foltyn; Bernhard Lesch; Gregor Bahrenberg; Hannelore Stockhausen; Thomas Christoph; Jeewoo Lee

doi:10.1016/j.bmcl.2021.128266

2-(Halogenated Phenyl) acetamides and propanamides as potent TRPV1 antagonists

Jin Mi Kang, Sun Ok Kwon, Jihyae Ann, Sunho Lee, Changhoon Kim, Nayeon Do, Jin Ju Jeong, Peter M. Blumberg, Heejin Ha, Thi Ngoc Lan Vu, Sanghee Yoon, Sun Choi, Robert Frank-Foltyn, Bernhard Lesch, Gregor Bahrenberg, Hannelore Stockhausen, Thomas Christoph, Jeewoo Lee

Pharmaceutical Sciences

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

2 Scopus citations

Abstract

A series consisting of 117 2-(halogenated phenyl) acetamide and propanamide analogs were investigated as TRPV1 antagonists. The structure–activity analysis targeting their three pharmacophoric regions indicated that halogenated phenyl A-region analogs exhibited a broad functional profile ranging from agonism to antagonism. Among the compounds, antagonists 28 and 92 exhibited potent antagonism toward capsaicin for hTRPV1 with K_i[CAP] = 2.6 and 6.9 nM, respectively. Further, antagonist 92 displayed promising analgesic activity in vivo in both phases of the formalin mouse pain model. A molecular modeling study of 92 indicated that the two fluoro groups in the A-region made hydrophobic interactions with the receptor.

Original language	English
Article number	128266
Journal	Bioorganic and Medicinal Chemistry Letters
Volume	48
DOIs	https://doi.org/10.1016/j.bmcl.2021.128266
State	Published - 15 Sep 2021

Keywords

Analgesic
TRPV1 Antagonist
Vanilloid Receptor 1

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10.1016/j.bmcl.2021.128266

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Kang, J. M., Kwon, S. O., Ann, J., Lee, S., Kim, C., Do, N., Jeong, J. J., Blumberg, P. M., Ha, H., Vu, T. N. L., Yoon, S., Choi, S., Frank-Foltyn, R., Lesch, B., Bahrenberg, G., Stockhausen, H., Christoph, T., & Lee, J. (2021). 2-(Halogenated Phenyl) acetamides and propanamides as potent TRPV1 antagonists. Bioorganic and Medicinal Chemistry Letters, 48, [128266]. https://doi.org/10.1016/j.bmcl.2021.128266

@article{293177d25027484d967b8d9e99c1140f,

title = "2-(Halogenated Phenyl) acetamides and propanamides as potent TRPV1 antagonists",

abstract = "A series consisting of 117 2-(halogenated phenyl) acetamide and propanamide analogs were investigated as TRPV1 antagonists. The structure–activity analysis targeting their three pharmacophoric regions indicated that halogenated phenyl A-region analogs exhibited a broad functional profile ranging from agonism to antagonism. Among the compounds, antagonists 28 and 92 exhibited potent antagonism toward capsaicin for hTRPV1 with Ki[CAP] = 2.6 and 6.9 nM, respectively. Further, antagonist 92 displayed promising analgesic activity in vivo in both phases of the formalin mouse pain model. A molecular modeling study of 92 indicated that the two fluoro groups in the A-region made hydrophobic interactions with the receptor.",

keywords = "Analgesic, TRPV1 Antagonist, Vanilloid Receptor 1",

author = "Kang, {Jin Mi} and Kwon, {Sun Ok} and Jihyae Ann and Sunho Lee and Changhoon Kim and Nayeon Do and Jeong, {Jin Ju} and Blumberg, {Peter M.} and Heejin Ha and Vu, {Thi Ngoc Lan} and Sanghee Yoon and Sun Choi and Robert Frank-Foltyn and Bernhard Lesch and Gregor Bahrenberg and Hannelore Stockhausen and Thomas Christoph and Jeewoo Lee",

note = "Funding Information: This work was supported by the Midcareer Researcher Program (NRF-2019R1A2C2006837 and NRF-2020R1A2C2101636) funded by the National Research Foundation of Korea (NRF). Publisher Copyright: {\textcopyright} 2021 Elsevier Ltd",

year = "2021",

month = sep,

day = "15",

doi = "10.1016/j.bmcl.2021.128266",

language = "English",

volume = "48",

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Kang, JM, Kwon, SO, Ann, J, Lee, S, Kim, C, Do, N, Jeong, JJ, Blumberg, PM, Ha, H, Vu, TNL, Yoon, S, Choi, S, Frank-Foltyn, R, Lesch, B, Bahrenberg, G, Stockhausen, H, Christoph, T & Lee, J 2021, '2-(Halogenated Phenyl) acetamides and propanamides as potent TRPV1 antagonists', Bioorganic and Medicinal Chemistry Letters, vol. 48, 128266. https://doi.org/10.1016/j.bmcl.2021.128266

TY - JOUR

T1 - 2-(Halogenated Phenyl) acetamides and propanamides as potent TRPV1 antagonists

AU - Kang, Jin Mi

AU - Kwon, Sun Ok

AU - Ann, Jihyae

AU - Lee, Sunho

AU - Kim, Changhoon

AU - Do, Nayeon

AU - Jeong, Jin Ju

AU - Blumberg, Peter M.

AU - Ha, Heejin

AU - Vu, Thi Ngoc Lan

AU - Yoon, Sanghee

AU - Choi, Sun

AU - Frank-Foltyn, Robert

AU - Lesch, Bernhard

AU - Bahrenberg, Gregor

AU - Stockhausen, Hannelore

AU - Christoph, Thomas

AU - Lee, Jeewoo

N1 - Funding Information: This work was supported by the Midcareer Researcher Program (NRF-2019R1A2C2006837 and NRF-2020R1A2C2101636) funded by the National Research Foundation of Korea (NRF). Publisher Copyright: © 2021 Elsevier Ltd

PY - 2021/9/15

Y1 - 2021/9/15

N2 - A series consisting of 117 2-(halogenated phenyl) acetamide and propanamide analogs were investigated as TRPV1 antagonists. The structure–activity analysis targeting their three pharmacophoric regions indicated that halogenated phenyl A-region analogs exhibited a broad functional profile ranging from agonism to antagonism. Among the compounds, antagonists 28 and 92 exhibited potent antagonism toward capsaicin for hTRPV1 with Ki[CAP] = 2.6 and 6.9 nM, respectively. Further, antagonist 92 displayed promising analgesic activity in vivo in both phases of the formalin mouse pain model. A molecular modeling study of 92 indicated that the two fluoro groups in the A-region made hydrophobic interactions with the receptor.

AB - A series consisting of 117 2-(halogenated phenyl) acetamide and propanamide analogs were investigated as TRPV1 antagonists. The structure–activity analysis targeting their three pharmacophoric regions indicated that halogenated phenyl A-region analogs exhibited a broad functional profile ranging from agonism to antagonism. Among the compounds, antagonists 28 and 92 exhibited potent antagonism toward capsaicin for hTRPV1 with Ki[CAP] = 2.6 and 6.9 nM, respectively. Further, antagonist 92 displayed promising analgesic activity in vivo in both phases of the formalin mouse pain model. A molecular modeling study of 92 indicated that the two fluoro groups in the A-region made hydrophobic interactions with the receptor.

KW - Analgesic

KW - TRPV1 Antagonist

KW - Vanilloid Receptor 1

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JO - Bioorganic and Medicinal Chemistry Letters

JF - Bioorganic and Medicinal Chemistry Letters

M1 - 128266

ER -

2-(Halogenated Phenyl) acetamides and propanamides as potent TRPV1 antagonists

Abstract

Keywords

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