α-Substituted 2-(3-fluoro-4-methylsulfonamidophenyl)acetamides as potent TRPV1 antagonists

Phuong Thao Tran; Ho Shin Kim; Jihyae Ann; Sung Eun Kim; Changhoon Kim; Mannkyu Hong; Van Hai Hoang; Van T.H. Ngo; Sunhye Hong; Minghua Cui; Sun Choi; Peter M. Blumberg; Robert Frank-Foltyn; Gregor Bahrenberg; Hannelore Stockhausen; Thomas Christoph; Jeewoo Lee

doi:10.1016/j.bmcl.2015.04.024

α-Substituted 2-(3-fluoro-4-methylsulfonamidophenyl)acetamides as potent TRPV1 antagonists

Phuong Thao Tran, Ho Shin Kim, Jihyae Ann, Sung Eun Kim, Changhoon Kim, Mannkyu Hong, Van Hai Hoang, Van T.H. Ngo, 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

11 Scopus citations

Abstract

A series of α-substituted acetamide derivatives of previously reported 2-(3-fluoro-4-methylsulfonamidophenyl)propanamide leads (1, 2) were investigated for antagonism of hTRPV1 activation by capsaicin. Compound 34, which possesses an α-m-tolyl substituent, showed highly potent and selective antagonism of capsaicin with K_i(CAP) = 0.1 nM. It thus reflected a 3-fold improvement in potency over parent 1. Docking analysis using our homology model indicated that the high potency of 34 might be attributed to a specific hydrophobic interaction of the m-tolyl group with the receptor.

Original language	English
Article number	22607
Pages (from-to)	2326-2330
Number of pages	5
Journal	Bioorganic and Medicinal Chemistry Letters
Volume	25
Issue number	11
DOIs	https://doi.org/10.1016/j.bmcl.2015.04.024
State	Published - 1 Jun 2015

Bibliographical note

Funding Information:
This research was supported by Research Grants from Grunenthal in Germany, Grants from the Korea Science and Engineering Foundation (KOSEF) ( NRF-2014M3A9B5073755 ) and National Leading Research Lab ( NLRL ) program ( 2011-0028885 ) in South Korea, and in part by the Intramural Research Program of NIH , Center for Cancer Research, NCI (Project Z1A BC 005270) in USA.

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

Keywords

Analgesic
Capsaicin
Molecular modeling
TRPV1 antagonist

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10.1016/j.bmcl.2015.04.024

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Tran, P. T., Kim, H. S., Ann, J., Kim, S. E., Kim, C., Hong, M., Hoang, V. H., Ngo, V. T. H., Hong, S., Cui, M., Choi, S., Blumberg, P. M., Frank-Foltyn, R., Bahrenberg, G., Stockhausen, H., Christoph, T., & Lee, J. (2015). α-Substituted 2-(3-fluoro-4-methylsulfonamidophenyl)acetamides as potent TRPV1 antagonists. Bioorganic and Medicinal Chemistry Letters, 25(11), 2326-2330. Article 22607. https://doi.org/10.1016/j.bmcl.2015.04.024

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title = "α-Substituted 2-(3-fluoro-4-methylsulfonamidophenyl)acetamides as potent TRPV1 antagonists",

abstract = "A series of α-substituted acetamide derivatives of previously reported 2-(3-fluoro-4-methylsulfonamidophenyl)propanamide leads (1, 2) were investigated for antagonism of hTRPV1 activation by capsaicin. Compound 34, which possesses an α-m-tolyl substituent, showed highly potent and selective antagonism of capsaicin with Ki(CAP) = 0.1 nM. It thus reflected a 3-fold improvement in potency over parent 1. Docking analysis using our homology model indicated that the high potency of 34 might be attributed to a specific hydrophobic interaction of the m-tolyl group with the receptor.",

keywords = "Analgesic, Capsaicin, Molecular modeling, TRPV1 antagonist",

author = "Tran, {Phuong Thao} and Kim, {Ho Shin} and Jihyae Ann and Kim, {Sung Eun} and Changhoon Kim and Mannkyu Hong and Hoang, {Van Hai} and Ngo, {Van T.H.} 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 Grunenthal in Germany, Grants from the Korea Science and Engineering Foundation (KOSEF) ( NRF-2014M3A9B5073755 ) and National Leading Research Lab ( NLRL ) program ( 2011-0028885 ) in South Korea, and in part by the Intramural Research Program of NIH , Center for Cancer Research, NCI (Project Z1A BC 005270) in USA. Publisher Copyright: {\textcopyright} 2015 Elsevier Ltd. All rights reserved.",

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doi = "10.1016/j.bmcl.2015.04.024",

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Tran, PT, Kim, HS, Ann, J, Kim, SE, Kim, C, Hong, M, Hoang, VH, Ngo, VTH, Hong, S, Cui, M, Choi, S, Blumberg, PM, Frank-Foltyn, R, Bahrenberg, G, Stockhausen, H, Christoph, T & Lee, J 2015, 'α-Substituted 2-(3-fluoro-4-methylsulfonamidophenyl)acetamides as potent TRPV1 antagonists', Bioorganic and Medicinal Chemistry Letters, vol. 25, no. 11, 22607, pp. 2326-2330. https://doi.org/10.1016/j.bmcl.2015.04.024

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T1 - α-Substituted 2-(3-fluoro-4-methylsulfonamidophenyl)acetamides as potent TRPV1 antagonists

AU - Tran, Phuong Thao

AU - Kim, Ho Shin

AU - Ann, Jihyae

AU - Kim, Sung Eun

AU - Kim, Changhoon

AU - Hong, Mannkyu

AU - Hoang, Van Hai

AU - Ngo, Van T.H.

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 Grunenthal in Germany, Grants from the Korea Science and Engineering Foundation (KOSEF) ( NRF-2014M3A9B5073755 ) and National Leading Research Lab ( NLRL ) program ( 2011-0028885 ) in South Korea, and in part by the Intramural Research Program of NIH , Center for Cancer Research, NCI (Project Z1A BC 005270) in USA. Publisher Copyright: © 2015 Elsevier Ltd. All rights reserved.

PY - 2015/6/1

Y1 - 2015/6/1

N2 - A series of α-substituted acetamide derivatives of previously reported 2-(3-fluoro-4-methylsulfonamidophenyl)propanamide leads (1, 2) were investigated for antagonism of hTRPV1 activation by capsaicin. Compound 34, which possesses an α-m-tolyl substituent, showed highly potent and selective antagonism of capsaicin with Ki(CAP) = 0.1 nM. It thus reflected a 3-fold improvement in potency over parent 1. Docking analysis using our homology model indicated that the high potency of 34 might be attributed to a specific hydrophobic interaction of the m-tolyl group with the receptor.

AB - A series of α-substituted acetamide derivatives of previously reported 2-(3-fluoro-4-methylsulfonamidophenyl)propanamide leads (1, 2) were investigated for antagonism of hTRPV1 activation by capsaicin. Compound 34, which possesses an α-m-tolyl substituent, showed highly potent and selective antagonism of capsaicin with Ki(CAP) = 0.1 nM. It thus reflected a 3-fold improvement in potency over parent 1. Docking analysis using our homology model indicated that the high potency of 34 might be attributed to a specific hydrophobic interaction of the m-tolyl group with the receptor.

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IS - 11

M1 - 22607

ER -

α-Substituted 2-(3-fluoro-4-methylsulfonamidophenyl)acetamides as potent TRPV1 antagonists

Abstract

Bibliographical note

Keywords

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