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 | |
| Publication status | Published - 13 Jun 2013 |
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Keywords
- rhythms
- ligand
- GSK4112
- beta
- cells
- modulation
- circadian behaviour
- metabolism
- macrophages
- clock
Cite this
}
Optimized chemical probes for REV-ERB alpha. / Trump, Ryan P.; Bresciani, Stefano; Cooper, Anthony W. J.; Tellam, James P.; Wojno, Justyna; Blaikley, John; Orband-Miller, Lisa A.; Kashatus, Jennifer A.; Boudjelal, Mohamed; Dawson, Helen C.; Loudon, Andrew; Ray, David; Grant, Daniel; Farrow, Stuart N.; Willson, Timothy M.; Tomkinson, Nicholas C. O.
In: Journal of Medicinal Chemistry, Vol. 56, No. 11, 13.06.2013, p. 4729-4737.Research output: Contribution to journal › Article
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
N2 - 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.
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
UR - http://www.scopus.com/inward/record.url?scp=84879044621&partnerID=8YFLogxK
U2 - 10.1021/jm400458q
DO - 10.1021/jm400458q
M3 - Article
VL - 56
SP - 4729
EP - 4737
JO - Journal of Medicinal Chemistry
JF - Journal of Medicinal Chemistry
SN - 0022-2623
IS - 11
ER -