title: Optimized chemical probes for REV-ERBα.
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.
authors: Molecular Discovery Research, GlaxoSmithKline, Research Triangle Park, North Carolina 27709-3398, USA. ryan.p.trump@gsk.com
authors: Ryan P
authors: RP
authors: Trump
authors: Stefano
authors: S
authors: Bresciani
authors: Anthony W J
authors: AW
authors: Cooper
authors: James P
authors: JP
authors: Tellam
authors: Justyna
authors: J
authors: Wojno
authors: John
authors: J
authors: Blaikley
authors: Lisa A
authors: LA
authors: Orband-Miller
authors: Jennifer A
authors: JA
authors: Kashatus
authors: Mohamed
authors: M
authors: Boudjelal
authors: Helen C
authors: HC
authors: Dawson
authors: Andrew
authors: A
authors: Loudon
authors: David
authors: D
authors: Ray
authors: Daniel
authors: D
authors: Grant
authors: Stuart N
authors: SN
authors: Farrow
authors: Timothy M
authors: TM
authors: Willson
authors: Nicholas C O
authors: NC
authors: Tomkinson
mesh_terms: D000588:Amines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D001682:Biological Availability; D002352:Carrier Proteins / Q000378:metabolism; D002460:Cell Line; D002940:Circadian Rhythm; D005998:Glycine / Q000031:analogs & derivatives / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D000071518:Liver X Receptors; D051379:Mice; D008810:Mice, Inbred C57BL; D056953:Nuclear Receptor Subfamily 1, Group D, Member 1 / Q000819:agonists*; D057093:Orphan Nuclear Receptors / Q000378:metabolism; D010446:Peptide Fragments / Q000378:metabolism; D016601:RNA-Binding Proteins; D011869:Radioligand Assay; D013329:Structure-Activity Relationship; D013876:Thiophenes / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology
chemical_list: D000588:Amines; D002352:Carrier Proteins; C572356:GSK4112; D000071518:Liver X Receptors; C064353:NR1D1 protein, human; C000605213:NR1H3 protein, human; C000605214:Nr1h3 protein, mouse; D056953:Nuclear Receptor Subfamily 1, Group D, Member 1; D057093:Orphan Nuclear Receptors; C455622:PPARGC1B protein, human; D010446:Peptide Fragments; D016601:RNA-Binding Proteins; D013876:Thiophenes; D005998:Glycine
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