2-(3-Fluoro-4-methylsulfonylaminophenyl)propanamides as potent TRPV1 antagonists: Structure activity relationships of the 2-oxy pyridine C-region

Shivaji A. Thorat; Dong Wook Kang; Hyungchul Ryu; Myeong Seop Kim; Ho Shin Kim; Jihyae Ann; Taehwan Ha; Sung Eun Kim; Karam Son; Sun Choi; Peter M. Blumberg; Robert Frank; Gregor Bahrenberg; Klaus Schiene; Thomas Christoph; Jeewoo Lee

doi:10.1016/j.ejmech.2013.04.003

2-(3-Fluoro-4-methylsulfonylaminophenyl)propanamides as potent TRPV1 antagonists: Structure activity relationships of the 2-oxy pyridine C-region

Shivaji A. Thorat, Dong Wook Kang, Hyungchul Ryu, Myeong Seop Kim, Ho Shin Kim, Jihyae Ann, Taehwan Ha, Sung Eun Kim, Karam Son, Sun Choi, Peter M. Blumberg, Robert Frank, Gregor Bahrenberg, Klaus Schiene, Thomas Christoph, Jeewoo Lee

Department of Pharmaceutical Sciences

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

22 Scopus citations

Abstract

The structure activity relationships of 2-oxy pyridine derivatives in the C-region of N-(6-trifluoromethyl-pyridin-3-ylmethyl) 2-(3-fluoro-4- methylsulfonylaminophenyl)propanamides as hTRPV1 antagonists were investigated. The analysis indicated that the lipophilicity of the 2-oxy substituents was critical for potent antagonism and 4 or 5 carbons appeared to be optimal for activity. Multiple compounds proved to have comparable activity to 1, which had been reported as the most potent antagonist for capsaicin activity among the previous series of compounds. Further analysis of compounds 22 (2-isobutyloxy) and 53 (2-benzyloxy) in the formalin test in mice demonstrated strong analgesic activity with full efficacy. Docking analysis of 53S using our hTRPV1 homology model indicated that the A- and B-region 2-(3-fluoro-4- methylsulfonylaminophenyl)propanamide made important hydrophobic and hydrogen bonding interactions with Tyr511 and that the C-region 6-trifluoromethyl and 2-benzyloxy groups of pyridine occupied the two hydrophobic binding pockets, respectively.

Original language	English
Pages (from-to)	589-602
Number of pages	14
Journal	European Journal of Medicinal Chemistry
Volume	64
DOIs	https://doi.org/10.1016/j.ejmech.2013.04.003
State	Published - 2013

Bibliographical note

Funding Information:
This research was supported by Research Grants from Grunenthal, Grants from the National Research Foundation of Korea (NRF) ( R11-2007-107-02001-0 ), Grants from the National Leading Research Lab (NLRL) program ( 2011-0028885 ), the Ewha Global Top 5 Grant 2011 and in part by the Intramural Research Program of NIH , Center for Cancer Research, NCI (Project Z1A BC 005270 ).

Keywords

Analgesic
Capsaicin
Molecular modeling
TRPV1 antagonists

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10.1016/j.ejmech.2013.04.003

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Thorat, S. A., Kang, D. W., Ryu, H., Kim, M. S., Kim, H. S., Ann, J., Ha, T., Kim, S. E., Son, K., Choi, S., Blumberg, P. M., Frank, R., Bahrenberg, G., Schiene, K., Christoph, T., & Lee, J. (2013). 2-(3-Fluoro-4-methylsulfonylaminophenyl)propanamides as potent TRPV1 antagonists: Structure activity relationships of the 2-oxy pyridine C-region. European Journal of Medicinal Chemistry, 64, 589-602. https://doi.org/10.1016/j.ejmech.2013.04.003

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title = "2-(3-Fluoro-4-methylsulfonylaminophenyl)propanamides as potent TRPV1 antagonists: Structure activity relationships of the 2-oxy pyridine C-region",

abstract = "The structure activity relationships of 2-oxy pyridine derivatives in the C-region of N-(6-trifluoromethyl-pyridin-3-ylmethyl) 2-(3-fluoro-4- methylsulfonylaminophenyl)propanamides as hTRPV1 antagonists were investigated. The analysis indicated that the lipophilicity of the 2-oxy substituents was critical for potent antagonism and 4 or 5 carbons appeared to be optimal for activity. Multiple compounds proved to have comparable activity to 1, which had been reported as the most potent antagonist for capsaicin activity among the previous series of compounds. Further analysis of compounds 22 (2-isobutyloxy) and 53 (2-benzyloxy) in the formalin test in mice demonstrated strong analgesic activity with full efficacy. Docking analysis of 53S using our hTRPV1 homology model indicated that the A- and B-region 2-(3-fluoro-4- methylsulfonylaminophenyl)propanamide made important hydrophobic and hydrogen bonding interactions with Tyr511 and that the C-region 6-trifluoromethyl and 2-benzyloxy groups of pyridine occupied the two hydrophobic binding pockets, respectively.",

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

author = "Thorat, {Shivaji A.} and Kang, {Dong Wook} and Hyungchul Ryu and Kim, {Myeong Seop} and Kim, {Ho Shin} and Jihyae Ann and Taehwan Ha and Kim, {Sung Eun} and Karam Son and Sun Choi and Blumberg, {Peter M.} and Robert Frank and Gregor Bahrenberg and Klaus Schiene and Thomas Christoph and Jeewoo Lee",

note = "Funding Information: This research was supported by Research Grants from Grunenthal, Grants from the National Research Foundation of Korea (NRF) ( R11-2007-107-02001-0 ), Grants from the National Leading Research Lab (NLRL) program ( 2011-0028885 ), the Ewha Global Top 5 Grant 2011 and in part by the Intramural Research Program of NIH , Center for Cancer Research, NCI (Project Z1A BC 005270 ).",

year = "2013",

doi = "10.1016/j.ejmech.2013.04.003",

language = "English",

volume = "64",

pages = "589--602",

journal = "European Journal of Medicinal Chemistry",

issn = "0223-5234",

publisher = "Elsevier Masson s.r.l.",

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Thorat, SA, Kang, DW, Ryu, H, Kim, MS, Kim, HS, Ann, J, Ha, T, Kim, SE, Son, K, Choi, S, Blumberg, PM, Frank, R, Bahrenberg, G, Schiene, K, Christoph, T & Lee, J 2013, '2-(3-Fluoro-4-methylsulfonylaminophenyl)propanamides as potent TRPV1 antagonists: Structure activity relationships of the 2-oxy pyridine C-region', European Journal of Medicinal Chemistry, vol. 64, pp. 589-602. https://doi.org/10.1016/j.ejmech.2013.04.003

TY - JOUR

T1 - 2-(3-Fluoro-4-methylsulfonylaminophenyl)propanamides as potent TRPV1 antagonists

T2 - Structure activity relationships of the 2-oxy pyridine C-region

AU - Thorat, Shivaji A.

AU - Kang, Dong Wook

AU - Ryu, Hyungchul

AU - Kim, Myeong Seop

AU - Kim, Ho Shin

AU - Ann, Jihyae

AU - Ha, Taehwan

AU - Kim, Sung Eun

AU - Son, Karam

AU - Choi, Sun

AU - Blumberg, Peter M.

AU - Frank, Robert

AU - Bahrenberg, Gregor

AU - Schiene, Klaus

AU - Christoph, Thomas

AU - Lee, Jeewoo

N1 - Funding Information: This research was supported by Research Grants from Grunenthal, Grants from the National Research Foundation of Korea (NRF) ( R11-2007-107-02001-0 ), Grants from the National Leading Research Lab (NLRL) program ( 2011-0028885 ), the Ewha Global Top 5 Grant 2011 and in part by the Intramural Research Program of NIH , Center for Cancer Research, NCI (Project Z1A BC 005270 ).

PY - 2013

Y1 - 2013

N2 - The structure activity relationships of 2-oxy pyridine derivatives in the C-region of N-(6-trifluoromethyl-pyridin-3-ylmethyl) 2-(3-fluoro-4- methylsulfonylaminophenyl)propanamides as hTRPV1 antagonists were investigated. The analysis indicated that the lipophilicity of the 2-oxy substituents was critical for potent antagonism and 4 or 5 carbons appeared to be optimal for activity. Multiple compounds proved to have comparable activity to 1, which had been reported as the most potent antagonist for capsaicin activity among the previous series of compounds. Further analysis of compounds 22 (2-isobutyloxy) and 53 (2-benzyloxy) in the formalin test in mice demonstrated strong analgesic activity with full efficacy. Docking analysis of 53S using our hTRPV1 homology model indicated that the A- and B-region 2-(3-fluoro-4- methylsulfonylaminophenyl)propanamide made important hydrophobic and hydrogen bonding interactions with Tyr511 and that the C-region 6-trifluoromethyl and 2-benzyloxy groups of pyridine occupied the two hydrophobic binding pockets, respectively.

AB - The structure activity relationships of 2-oxy pyridine derivatives in the C-region of N-(6-trifluoromethyl-pyridin-3-ylmethyl) 2-(3-fluoro-4- methylsulfonylaminophenyl)propanamides as hTRPV1 antagonists were investigated. The analysis indicated that the lipophilicity of the 2-oxy substituents was critical for potent antagonism and 4 or 5 carbons appeared to be optimal for activity. Multiple compounds proved to have comparable activity to 1, which had been reported as the most potent antagonist for capsaicin activity among the previous series of compounds. Further analysis of compounds 22 (2-isobutyloxy) and 53 (2-benzyloxy) in the formalin test in mice demonstrated strong analgesic activity with full efficacy. Docking analysis of 53S using our hTRPV1 homology model indicated that the A- and B-region 2-(3-fluoro-4- methylsulfonylaminophenyl)propanamide made important hydrophobic and hydrogen bonding interactions with Tyr511 and that the C-region 6-trifluoromethyl and 2-benzyloxy groups of pyridine occupied the two hydrophobic binding pockets, respectively.

KW - Analgesic

KW - Capsaicin

KW - Molecular modeling

KW - TRPV1 antagonists

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U2 - 10.1016/j.ejmech.2013.04.003

DO - 10.1016/j.ejmech.2013.04.003

M3 - Article

C2 - 23685943

AN - SCOPUS:84879017091

SN - 0223-5234

VL - 64

SP - 589

EP - 602

JO - European Journal of Medicinal Chemistry

JF - European Journal of Medicinal Chemistry

ER -

2-(3-Fluoro-4-methylsulfonylaminophenyl)propanamides as potent TRPV1 antagonists: Structure activity relationships of the 2-oxy pyridine C-region

Abstract

Bibliographical note

Keywords

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