Optimized chemical probes for REV-ERB alpha

Ryan P. Trump; Stefano Bresciani; Anthony W. J. Cooper; James P. Tellam; Justyna Wojno; John Blaikley; Lisa A. Orband-Miller; Jennifer A. Kashatus; Mohamed Boudjelal; Helen C. Dawson; Andrew Loudon; David Ray; Daniel Grant; Stuart N. Farrow; Timothy M. Willson; Nicholas C. O. Tomkinson

doi:10.1021/jm400458q

Optimized chemical probes for REV-ERB alpha

Ryan P. Trump, Stefano Bresciani, Anthony W. J. Cooper, James P. Tellam, Justyna Wojno, John Blaikley, Lisa A. Orband-Miller, Jennifer A. Kashatus, Mohamed Boudjelal, Helen C. Dawson, Andrew Loudon, David Ray, Daniel Grant, Stuart N. Farrow, Timothy M. Willson, Nicholas C. O. Tomkinson

Pure And Applied Chemistry

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

70 Citations (Scopus)

Abstract

REV-ERB alpha has emerged as an important target for regulation of circadian rhythm and its associated physiology. Herein, we report on the optimization of a series of REV-ERB alpha agonists based on G5K4112 (1) for potency, selectivity, and bioavailability.(1) Potent REV-ERB alpha agonists 4, 10, 16, and 23 are detailed for their ability to suppress BMAL and IL-6 expression from human cells while also demonstrating excellent selectivity over LAR alpha. Amine 4 demonstrated in vivo bioavailability after either iv or oral dosing.

Original language	English
Pages (from-to)	4729-4737
Number of pages	9
Journal	Journal of Medicinal Chemistry
Volume	56
Issue number	11
DOIs	https://doi.org/10.1021/jm400458q
Publication status	Published - 13 Jun 2013

Keywords

rhythms
ligand
GSK4112
beta
cells
modulation
circadian behaviour
metabolism
macrophages
clock

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10.1021/jm400458q

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Trump, R. P., Bresciani, S., Cooper, A. W. J., Tellam, J. P., Wojno, J., Blaikley, J., Orband-Miller, L. A., Kashatus, J. A., Boudjelal, M., Dawson, H. C., Loudon, A., Ray, D., Grant, D., Farrow, S. N., Willson, T. M., & Tomkinson, N. C. O. (2013). Optimized chemical probes for REV-ERB alpha. Journal of Medicinal Chemistry, 56(11), 4729-4737. https://doi.org/10.1021/jm400458q

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title = "Optimized chemical probes for REV-ERB alpha",

abstract = "REV-ERB alpha has emerged as an important target for regulation of circadian rhythm and its associated physiology. Herein, we report on the optimization of a series of REV-ERB alpha agonists based on G5K4112 (1) for potency, selectivity, and bioavailability.(1) Potent REV-ERB alpha agonists 4, 10, 16, and 23 are detailed for their ability to suppress BMAL and IL-6 expression from human cells while also demonstrating excellent selectivity over LAR alpha. Amine 4 demonstrated in vivo bioavailability after either iv or oral dosing.",

keywords = "rhythms, ligand, GSK4112, beta, cells, modulation, circadian behaviour, metabolism, macrophages, clock",

author = "Trump, {Ryan P.} and Stefano Bresciani and Cooper, {Anthony W. J.} and Tellam, {James P.} and Justyna Wojno and John Blaikley and Orband-Miller, {Lisa A.} and Kashatus, {Jennifer A.} and Mohamed Boudjelal and Dawson, {Helen C.} and Andrew Loudon and David Ray and Daniel Grant and Farrow, {Stuart N.} and Willson, {Timothy M.} and Tomkinson, {Nicholas C. O.}",

year = "2013",

month = jun,

day = "13",

doi = "10.1021/jm400458q",

language = "English",

volume = "56",

pages = "4729--4737",

journal = "Journal of Medicinal Chemistry",

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publisher = "American Chemical Society",

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TY - JOUR

T1 - Optimized chemical probes for REV-ERB alpha

AU - Trump, Ryan P.

AU - Bresciani, Stefano

AU - Cooper, Anthony W. J.

AU - Tellam, James P.

AU - Wojno, Justyna

AU - Blaikley, John

AU - Orband-Miller, Lisa A.

AU - Kashatus, Jennifer A.

AU - Boudjelal, Mohamed

AU - Dawson, Helen C.

AU - Loudon, Andrew

AU - Ray, David

AU - Grant, Daniel

AU - Farrow, Stuart N.

AU - Willson, Timothy M.

AU - Tomkinson, Nicholas C. O.

PY - 2013/6/13

Y1 - 2013/6/13

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AB - REV-ERB alpha has emerged as an important target for regulation of circadian rhythm and its associated physiology. Herein, we report on the optimization of a series of REV-ERB alpha agonists based on G5K4112 (1) for potency, selectivity, and bioavailability.(1) Potent REV-ERB alpha agonists 4, 10, 16, and 23 are detailed for their ability to suppress BMAL and IL-6 expression from human cells while also demonstrating excellent selectivity over LAR alpha. Amine 4 demonstrated in vivo bioavailability after either iv or oral dosing.

KW - rhythms

KW - ligand

KW - GSK4112

KW - beta

KW - cells

KW - modulation

KW - circadian behaviour

KW - metabolism

KW - macrophages

KW - clock

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U2 - 10.1021/jm400458q

DO - 10.1021/jm400458q

M3 - Article

SN - 0022-2623

VL - 56

SP - 4729

EP - 4737

JO - Journal of Medicinal Chemistry

JF - Journal of Medicinal Chemistry

IS - 11

ER -

Optimized chemical probes for REV-ERB alpha

Abstract

Keywords

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Optimized chemical probes for REV-ERB alpha

Abstract

Keywords

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SMSdrug.net: Alignment Of Synthesis, Medicinal Chemistry And Strucrural Genomics To Accelerate Uk Drug Discovery: Network SMS-Drug

Cite this