N-4-t-Butylbenzyl 2-(4-methylsulfonylaminophenyl) propanamide TRPV1 antagonists: Structure-activity relationships in the A-region

Yong Soo Kim; Min Jung Kil; Sang Uk Kang; Hyungchul Ryu; Myeong Seop Kim; Yongsung Cho; Rahul S. Bhondwe; Shivaji A. Thorat; Wei Sun; Keliang Liu; Jin Hee Lee; Sun Choi; Larry V. Pearce; Vladimir A. Pavlyukovets; Matthew A. Morgan; Richard Tran; Jozsef Lazar; Peter M. Blumberg; Jeewoo Lee

doi:10.1016/j.bmc.2011.11.008

N-4-t-Butylbenzyl 2-(4-methylsulfonylaminophenyl) propanamide TRPV1 antagonists: Structure-activity relationships in the A-region

Yong Soo Kim
, Min Jung Kil
, Sang Uk Kang
, Hyungchul Ryu
, Myeong Seop Kim
, Yongsung Cho
, Rahul S. Bhondwe
, Shivaji A. Thorat
, Wei Sun
, Keliang Liu
, Jin Hee Lee
, Sun Choi
, Larry V. Pearce
, Vladimir A. Pavlyukovets
, Matthew A. Morgan
, Richard Tran
, Jozsef Lazar
, Peter M. Blumberg
, Jeewoo Lee

Department of Pharmaceutical Sciences

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

12 Scopus citations

Abstract

Structure-activity relationships for the A-region in a series of N-4-t-butylbenzyl 2-(4-methylsulfonylaminophenyl) propanamides as TRPV1 antagonists have been investigated. Among them, the 3-fluoro analogue 54 showed high binding affinity and potent antagonism for both rTRPV1 and hTRPV1 in CHO cells. Its stereospecific activity was demonstrated with marked selectivity for the (S)-configuration (54S versus 54R). A docking study of 54S with our hTRPV1 homology model highlighted crucial hydrogen bonds between the ligand and the receptor contributing to its potency.

Original language	English
Pages (from-to)	215-224
Number of pages	10
Journal	Bioorganic and Medicinal Chemistry
Volume	20
Issue number	1
DOIs	https://doi.org/10.1016/j.bmc.2011.11.008
State	Published - 1 Jan 2012

Bibliographical note

Funding Information:
This research was supported by Research Funding from Digitalbiotech, Grants R11–2007–107–02001-0 from the National Research Foundation of Korea (NRF), the National Core Research Center (NCRC) program (No. 2011-0006244) of MEST and NRF through the Center for Cell Signaling & Drug Discovery Research at Ewha Womans University, and the intramural program of the National Institutes of Health, Center for Cancer Research, National Cancer Institute (project Z1A BC 005270).

Keywords

Analgesic
Capsaicin
Molecular modeling
Resiniferatoxin
TRPV1 antagonists

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10.1016/j.bmc.2011.11.008

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Kim, Y. S., Kil, M. J., Kang, S. U., Ryu, H., Kim, M. S., Cho, Y., Bhondwe, R. S., Thorat, S. A., Sun, W., Liu, K., Lee, J. H., Choi, S., Pearce, L. V., Pavlyukovets, V. A., Morgan, M. A., Tran, R., Lazar, J., Blumberg, P. M., & Lee, J. (2012). N-4-t-Butylbenzyl 2-(4-methylsulfonylaminophenyl) propanamide TRPV1 antagonists: Structure-activity relationships in the A-region. Bioorganic and Medicinal Chemistry, 20(1), 215-224. https://doi.org/10.1016/j.bmc.2011.11.008

@article{8fe80618aafc4371b0dc2b69f45d8351,

title = "N-4-t-Butylbenzyl 2-(4-methylsulfonylaminophenyl) propanamide TRPV1 antagonists: Structure-activity relationships in the A-region",

abstract = "Structure-activity relationships for the A-region in a series of N-4-t-butylbenzyl 2-(4-methylsulfonylaminophenyl) propanamides as TRPV1 antagonists have been investigated. Among them, the 3-fluoro analogue 54 showed high binding affinity and potent antagonism for both rTRPV1 and hTRPV1 in CHO cells. Its stereospecific activity was demonstrated with marked selectivity for the (S)-configuration (54S versus 54R). A docking study of 54S with our hTRPV1 homology model highlighted crucial hydrogen bonds between the ligand and the receptor contributing to its potency.",

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

author = "Kim, \{Yong Soo\} and Kil, \{Min Jung\} and Kang, \{Sang Uk\} and Hyungchul Ryu and Kim, \{Myeong Seop\} and Yongsung Cho and Bhondwe, \{Rahul S.\} and Thorat, \{Shivaji A.\} and Wei Sun and Keliang Liu and Lee, \{Jin Hee\} and Sun Choi and Pearce, \{Larry V.\} and Pavlyukovets, \{Vladimir A.\} and Morgan, \{Matthew A.\} and Richard Tran and Jozsef Lazar and Blumberg, \{Peter M.\} and Jeewoo Lee",

note = "Funding Information: This research was supported by Research Funding from Digitalbiotech, Grants R11–2007–107–02001-0 from the National Research Foundation of Korea (NRF), the National Core Research Center (NCRC) program (No. 2011-0006244) of MEST and NRF through the Center for Cell Signaling \& Drug Discovery Research at Ewha Womans University, and the intramural program of the National Institutes of Health, Center for Cancer Research, National Cancer Institute (project Z1A BC 005270).",

year = "2012",

month = jan,

day = "1",

doi = "10.1016/j.bmc.2011.11.008",

language = "English",

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Kim, YS, Kil, MJ, Kang, SU, Ryu, H, Kim, MS, Cho, Y, Bhondwe, RS, Thorat, SA, Sun, W, Liu, K, Lee, JH, Choi, S, Pearce, LV, Pavlyukovets, VA, Morgan, MA, Tran, R, Lazar, J, Blumberg, PM & Lee, J 2012, 'N-4-t-Butylbenzyl 2-(4-methylsulfonylaminophenyl) propanamide TRPV1 antagonists: Structure-activity relationships in the A-region', Bioorganic and Medicinal Chemistry, vol. 20, no. 1, pp. 215-224. https://doi.org/10.1016/j.bmc.2011.11.008

TY - JOUR

T1 - N-4-t-Butylbenzyl 2-(4-methylsulfonylaminophenyl) propanamide TRPV1 antagonists

T2 - Structure-activity relationships in the A-region

AU - Kim, Yong Soo

AU - Kil, Min Jung

AU - Kang, Sang Uk

AU - Ryu, Hyungchul

AU - Kim, Myeong Seop

AU - Cho, Yongsung

AU - Bhondwe, Rahul S.

AU - Thorat, Shivaji A.

AU - Sun, Wei

AU - Liu, Keliang

AU - Lee, Jin Hee

AU - Choi, Sun

AU - Pearce, Larry V.

AU - Pavlyukovets, Vladimir A.

AU - Morgan, Matthew A.

AU - Tran, Richard

AU - Lazar, Jozsef

AU - Blumberg, Peter M.

AU - Lee, Jeewoo

N1 - Funding Information: This research was supported by Research Funding from Digitalbiotech, Grants R11–2007–107–02001-0 from the National Research Foundation of Korea (NRF), the National Core Research Center (NCRC) program (No. 2011-0006244) of MEST and NRF through the Center for Cell Signaling & Drug Discovery Research at Ewha Womans University, and the intramural program of the National Institutes of Health, Center for Cancer Research, National Cancer Institute (project Z1A BC 005270).

PY - 2012/1/1

Y1 - 2012/1/1

N2 - Structure-activity relationships for the A-region in a series of N-4-t-butylbenzyl 2-(4-methylsulfonylaminophenyl) propanamides as TRPV1 antagonists have been investigated. Among them, the 3-fluoro analogue 54 showed high binding affinity and potent antagonism for both rTRPV1 and hTRPV1 in CHO cells. Its stereospecific activity was demonstrated with marked selectivity for the (S)-configuration (54S versus 54R). A docking study of 54S with our hTRPV1 homology model highlighted crucial hydrogen bonds between the ligand and the receptor contributing to its potency.

AB - Structure-activity relationships for the A-region in a series of N-4-t-butylbenzyl 2-(4-methylsulfonylaminophenyl) propanamides as TRPV1 antagonists have been investigated. Among them, the 3-fluoro analogue 54 showed high binding affinity and potent antagonism for both rTRPV1 and hTRPV1 in CHO cells. Its stereospecific activity was demonstrated with marked selectivity for the (S)-configuration (54S versus 54R). A docking study of 54S with our hTRPV1 homology model highlighted crucial hydrogen bonds between the ligand and the receptor contributing to its potency.

KW - Analgesic

KW - Capsaicin

KW - Molecular modeling

KW - Resiniferatoxin

KW - TRPV1 antagonists

UR - https://www.scopus.com/pages/publications/84855188641

U2 - 10.1016/j.bmc.2011.11.008

DO - 10.1016/j.bmc.2011.11.008

M3 - Article

C2 - 22169633

AN - SCOPUS:84855188641

SN - 0968-0896

VL - 20

SP - 215

EP - 224

JO - Bioorganic and Medicinal Chemistry

JF - Bioorganic and Medicinal Chemistry

IS - 1

ER -

N-4-t-Butylbenzyl 2-(4-methylsulfonylaminophenyl) propanamide TRPV1 antagonists: Structure-activity relationships in the A-region

Abstract

Bibliographical note

Keywords

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