Discovery of substituted maleimides as liver X receptor agonists and determination of a ligand-bound crystal structure

M.C. Jaye; J.A. Krawiec; N. Campobasso; A. Smallwood; C.Y. Qiu; Q. Lu; J.J. Kerrigan; M.D.L. Alvaro; B. Laffitte; W.S. Liu; J.P. Marino; C.R. Meyer; J.A. Nichols; D.J. Parks; P. Perez; L. Sarov-Blat; S.D. Seepersaud; K.M. Steplewski; S.K. Thompson; P. Wang; M.A. Watson; C.L. Webb; David Haigh; J.A. Caravella; C.H. Macphee; T.M. Willson; J.L. Collins

doi:10.1021/jm050532w

Discovery of substituted maleimides as liver X receptor agonists and determination of a ligand-bound crystal structure

M.C. Jaye, J.A. Krawiec, N. Campobasso, A. Smallwood, C.Y. Qiu, Q. Lu, J.J. Kerrigan, M.D.L. Alvaro, B. Laffitte, W.S. Liu, J.P. Marino, C.R. Meyer, J.A. Nichols, D.J. Parks, P. Perez, L. Sarov-Blat, S.D. Seepersaud, K.M. Steplewski, S.K. Thompson, P. WangM.A. Watson, C.L. Webb, David Haigh, J.A. Caravella, C.H. Macphee, T.M. Willson, J.L. Collins

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Abstract

Substituted 3-(phenylamino)-1H-pyrrole-2,5-diones were identified from a high throughput screen as inducers of human ATP binding cassette transporter A1 expression. Mechanism of action studies led to the identification of GSK3987 (4) as an LXR ligand. 4 recruits the steroid receptor coactivator-1 to human LXR alpha and LXRP with EC(50)s of 40 nM, profiles as an LXR agonist in functional assays, and activates LXR though a mechanism that is similar to first generation LXR agonists.

Original language	English
Pages (from-to)	5419-5422
Number of pages	4
Journal	Journal of Medicinal Chemistry
Volume	48
Issue number	17
DOIs	https://doi.org/10.1021/jm050532w
Publication status	Published - 25 Aug 2005

ASJC Scopus subject areas

Organic Chemistry

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Jaye, M. C., Krawiec, J. A., Campobasso, N., Smallwood, A., Qiu, C. Y., Lu, Q., Kerrigan, J. J., Alvaro, M. D. L., Laffitte, B., Liu, W. S., Marino, J. P., Meyer, C. R., Nichols, J. A., Parks, D. J., Perez, P., Sarov-Blat, L., Seepersaud, S. D., Steplewski, K. M., Thompson, S. K., ... Collins, J. L. (2005). Discovery of substituted maleimides as liver X receptor agonists and determination of a ligand-bound crystal structure. Journal of Medicinal Chemistry, 48(17), 5419-5422. https://doi.org/10.1021/jm050532w

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abstract = "Substituted 3-(phenylamino)-1H-pyrrole-2,5-diones were identified from a high throughput screen as inducers of human ATP binding cassette transporter A1 expression. Mechanism of action studies led to the identification of GSK3987 (4) as an LXR ligand. 4 recruits the steroid receptor coactivator-1 to human LXR alpha and LXRP with EC(50)s of 40 nM, profiles as an LXR agonist in functional assays, and activates LXR though a mechanism that is similar to first generation LXR agonists.",

author = "M.C. Jaye and J.A. Krawiec and N. Campobasso and A. Smallwood and C.Y. Qiu and Q. Lu and J.J. Kerrigan and M.D.L. Alvaro and B. Laffitte and W.S. Liu and J.P. Marino and C.R. Meyer and J.A. Nichols and D.J. Parks and P. Perez and L. Sarov-Blat and S.D. Seepersaud and K.M. Steplewski and S.K. Thompson and P. Wang and M.A. Watson and C.L. Webb and David Haigh and J.A. Caravella and C.H. Macphee and T.M. Willson and J.L. Collins",

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Jaye, MC, Krawiec, JA, Campobasso, N, Smallwood, A, Qiu, CY, Lu, Q, Kerrigan, JJ, Alvaro, MDL, Laffitte, B, Liu, WS, Marino, JP, Meyer, CR, Nichols, JA, Parks, DJ, Perez, P, Sarov-Blat, L, Seepersaud, SD, Steplewski, KM, Thompson, SK, Wang, P, Watson, MA, Webb, CL, Haigh, D, Caravella, JA, Macphee, CH, Willson, TM & Collins, JL 2005, 'Discovery of substituted maleimides as liver X receptor agonists and determination of a ligand-bound crystal structure', Journal of Medicinal Chemistry, vol. 48, no. 17, pp. 5419-5422. https://doi.org/10.1021/jm050532w

TY - JOUR

T1 - Discovery of substituted maleimides as liver X receptor agonists and determination of a ligand-bound crystal structure

AU - Jaye, M.C.

AU - Krawiec, J.A.

AU - Campobasso, N.

AU - Smallwood, A.

AU - Qiu, C.Y.

AU - Lu, Q.

AU - Kerrigan, J.J.

AU - Alvaro, M.D.L.

AU - Laffitte, B.

AU - Liu, W.S.

AU - Marino, J.P.

AU - Meyer, C.R.

AU - Nichols, J.A.

AU - Parks, D.J.

AU - Perez, P.

AU - Sarov-Blat, L.

AU - Seepersaud, S.D.

AU - Steplewski, K.M.

AU - Thompson, S.K.

AU - Wang, P.

AU - Watson, M.A.

AU - Webb, C.L.

AU - Haigh, David

AU - Caravella, J.A.

AU - Macphee, C.H.

AU - Willson, T.M.

AU - Collins, J.L.

PY - 2005/8/25

Y1 - 2005/8/25

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AB - Substituted 3-(phenylamino)-1H-pyrrole-2,5-diones were identified from a high throughput screen as inducers of human ATP binding cassette transporter A1 expression. Mechanism of action studies led to the identification of GSK3987 (4) as an LXR ligand. 4 recruits the steroid receptor coactivator-1 to human LXR alpha and LXRP with EC(50)s of 40 nM, profiles as an LXR agonist in functional assays, and activates LXR though a mechanism that is similar to first generation LXR agonists.

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DO - 10.1021/jm050532w

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JO - Journal of Medicinal Chemistry

JF - Journal of Medicinal Chemistry

IS - 17

ER -

Discovery of substituted maleimides as liver X receptor agonists and determination of a ligand-bound crystal structure

Abstract

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