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

Department of Pharmaceutical Sciences

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

7 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

Bibliographical note

Publisher Copyright:
© 2021 Elsevier Ltd

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, Article 128266. https://doi.org/10.1016/j.bmcl.2021.128266

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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",

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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

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

UR - https://www.scopus.com/pages/publications/85111013432

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DO - 10.1016/j.bmcl.2021.128266

M3 - Article

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AN - SCOPUS:85111013432

SN - 0960-894X

VL - 48

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

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Keywords

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