Structure-guided design of N-phenyl tertiary amines as transrepression- selective liver X receptor modulators with anti-inflammatory activity

Esther Y. Chao; Justin A. Caravella; Mike A. Watson; Nino Campobasso; Serena Ghisletti; Andrew N. Billin; Cristin Galardi; Ping Wang; Bryan A. Laffitte; Marie A. Iannone; Bryan J. Goodwin; Jason A. Nichols; Derek J. Parks; Eugene Stewart; Robert W. Wiethe; Shawn P. Williams; Angela Smallwood; Kenneth H. Pearce; Christopher K. Glass; Timothy M. Willson; William J. Zuercher; Jon L. Collins

doi:10.1021/jm800612u

Structure-guided design of N-phenyl tertiary amines as transrepression- selective liver X receptor modulators with anti-inflammatory activity

Esther Y. Chao, Justin A. Caravella, Mike A. Watson, Nino Campobasso, Serena Ghisletti, Andrew N. Billin, Cristin Galardi, Ping Wang, Bryan A. Laffitte, Marie A. Iannone, Bryan J. Goodwin, Jason A. Nichols, Derek J. Parks, Eugene Stewart, Robert W. Wiethe, Shawn P. Williams, Angela Smallwood, Kenneth H. Pearce, Christopher K. Glass, Timothy M. WillsonWilliam J. Zuercher, Jon L. Collins

Istituto Europeo di Oncologia

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

Abstract

A cocrystal structure of T1317 (3) bound to hLXRβ was utilized in the design of a series of substituted N-phenyl tertiary amines. Profiling in binding and functional assays led to the identification of LXR modulator GSK9772 (20) as a high-affinity LXRβ ligand (IC₅₀ = 30 nM) that shows separation of anti-inflammatory and lipogenic activities in human macrophage and liver cell lines, respectively. A cocrystal structure of the structurally related analog 19 bound to LXRβ reveals regions within the receptor that can affect receptor modulation through ligand modification. Mechanistic studies demonstrate that 20 is greater than 10-fold selective for LXR-mediated transrepression of proinflammatory gene expression versus transactivation of lipogenic signaling pathways, thus providing an opportunity for the identification of LXR modulators with improved therapeutic indexes.

Original language	English
Pages (from-to)	5758-5765
Number of pages	8
Journal	Journal of Medicinal Chemistry
Volume	51
Issue number	18
DOIs	https://doi.org/10.1021/jm800612u
Publication status	Published - Sept 25 2008

ASJC Scopus subject areas

Molecular Medicine
Drug Discovery

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10.1021/jm800612u

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Chao, E. Y., Caravella, J. A., Watson, M. A., Campobasso, N., Ghisletti, S., Billin, A. N., Galardi, C., Wang, P., Laffitte, B. A., Iannone, M. A., Goodwin, B. J., Nichols, J. A., Parks, D. J., Stewart, E., Wiethe, R. W., Williams, S. P., Smallwood, A., Pearce, K. H., Glass, C. K., ... Collins, J. L. (2008). Structure-guided design of N-phenyl tertiary amines as transrepression- selective liver X receptor modulators with anti-inflammatory activity. Journal of Medicinal Chemistry, 51(18), 5758-5765. https://doi.org/10.1021/jm800612u

Chao, EY, Caravella, JA, Watson, MA, Campobasso, N, Ghisletti, S, Billin, AN, Galardi, C, Wang, P, Laffitte, BA, Iannone, MA, Goodwin, BJ, Nichols, JA, Parks, DJ, Stewart, E, Wiethe, RW, Williams, SP, Smallwood, A, Pearce, KH, Glass, CK, Willson, TM, Zuercher, WJ & Collins, JL 2008, 'Structure-guided design of N-phenyl tertiary amines as transrepression- selective liver X receptor modulators with anti-inflammatory activity', Journal of Medicinal Chemistry, vol. 51, no. 18, pp. 5758-5765. https://doi.org/10.1021/jm800612u

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title = "Structure-guided design of N-phenyl tertiary amines as transrepression- selective liver X receptor modulators with anti-inflammatory activity",

abstract = "A cocrystal structure of T1317 (3) bound to hLXRβ was utilized in the design of a series of substituted N-phenyl tertiary amines. Profiling in binding and functional assays led to the identification of LXR modulator GSK9772 (20) as a high-affinity LXRβ ligand (IC50 = 30 nM) that shows separation of anti-inflammatory and lipogenic activities in human macrophage and liver cell lines, respectively. A cocrystal structure of the structurally related analog 19 bound to LXRβ reveals regions within the receptor that can affect receptor modulation through ligand modification. Mechanistic studies demonstrate that 20 is greater than 10-fold selective for LXR-mediated transrepression of proinflammatory gene expression versus transactivation of lipogenic signaling pathways, thus providing an opportunity for the identification of LXR modulators with improved therapeutic indexes.",

author = "Chao, {Esther Y.} and Caravella, {Justin A.} and Watson, {Mike A.} and Nino Campobasso and Serena Ghisletti and Billin, {Andrew N.} and Cristin Galardi and Ping Wang and Laffitte, {Bryan A.} and Iannone, {Marie A.} and Goodwin, {Bryan J.} and Nichols, {Jason A.} and Parks, {Derek J.} and Eugene Stewart and Wiethe, {Robert W.} and Williams, {Shawn P.} and Angela Smallwood and Pearce, {Kenneth H.} and Glass, {Christopher K.} and Willson, {Timothy M.} and Zuercher, {William J.} and Collins, {Jon L.}",

year = "2008",

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AU - Chao, Esther Y.

AU - Caravella, Justin A.

AU - Watson, Mike A.

AU - Campobasso, Nino

AU - Ghisletti, Serena

AU - Billin, Andrew N.

AU - Galardi, Cristin

AU - Wang, Ping

AU - Laffitte, Bryan A.

AU - Iannone, Marie A.

AU - Goodwin, Bryan J.

AU - Nichols, Jason A.

AU - Parks, Derek J.

AU - Stewart, Eugene

AU - Wiethe, Robert W.

AU - Williams, Shawn P.

AU - Smallwood, Angela

AU - Pearce, Kenneth H.

AU - Glass, Christopher K.

AU - Willson, Timothy M.

AU - Zuercher, William J.

AU - Collins, Jon L.

PY - 2008/9/25

Y1 - 2008/9/25

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AB - A cocrystal structure of T1317 (3) bound to hLXRβ was utilized in the design of a series of substituted N-phenyl tertiary amines. Profiling in binding and functional assays led to the identification of LXR modulator GSK9772 (20) as a high-affinity LXRβ ligand (IC50 = 30 nM) that shows separation of anti-inflammatory and lipogenic activities in human macrophage and liver cell lines, respectively. A cocrystal structure of the structurally related analog 19 bound to LXRβ reveals regions within the receptor that can affect receptor modulation through ligand modification. Mechanistic studies demonstrate that 20 is greater than 10-fold selective for LXR-mediated transrepression of proinflammatory gene expression versus transactivation of lipogenic signaling pathways, thus providing an opportunity for the identification of LXR modulators with improved therapeutic indexes.

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Structure-guided design of N-phenyl tertiary amines as transrepression- selective liver X receptor modulators with anti-inflammatory activity

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