Abstract
REV-ERBα 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-ERBα agonists based on GSK4112 (1) for potency, selectivity, and bioavailability. (1) Potent REV-ERBα 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 LXRα. Amine 4 demonstrated in vivo bioavailability after either iv or oral dosing.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Amines / chemical synthesis*
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Amines / chemistry
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Amines / pharmacology
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Animals
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Biological Availability
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Carrier Proteins / metabolism
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Cell Line
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Circadian Rhythm
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Glycine / analogs & derivatives
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Glycine / chemical synthesis
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Glycine / chemistry
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Glycine / pharmacology
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Humans
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Liver X Receptors
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Mice
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Mice, Inbred C57BL
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Nuclear Receptor Subfamily 1, Group D, Member 1 / agonists*
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Orphan Nuclear Receptors / metabolism
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Peptide Fragments / metabolism
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RNA-Binding Proteins
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Radioligand Assay
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Structure-Activity Relationship
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Thiophenes / chemical synthesis
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Thiophenes / chemistry
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Thiophenes / pharmacology
Substances
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Amines
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Carrier Proteins
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GSK4112
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Liver X Receptors
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NR1D1 protein, human
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NR1H3 protein, human
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Nr1h3 protein, mouse
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Nuclear Receptor Subfamily 1, Group D, Member 1
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Orphan Nuclear Receptors
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PPARGC1B protein, human
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Peptide Fragments
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RNA-Binding Proteins
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Thiophenes
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Glycine