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1.
Bioorg Med Chem Lett ; 28(7): 1178-1181, 2018 04 15.
Article in English | MEDLINE | ID: mdl-29534930

ABSTRACT

Crystallography has identified stearic acid, ALRT 1550 and ATRA as ligands that bind RORß, however, none of these molecules represent good starting points to develop optimized small molecule modulators. Recently, Compound 1 was identified as a potent dual RORß and RORγ inverse agonist with no activity towards RORα (Fig. 1). To our knowledge, this is one of only two small molecule RORß inverse agonists identified in the primary literature from a tractable chemical series and represents an ideal starting point from which to design RORß-selective modulators. Herein we describe our SAR optimization efforts that led to a series of potent neutral antagonists of RORß.


Subject(s)
Nuclear Receptor Subfamily 1, Group F, Member 2/agonists , Thiazoles/pharmacology , Dose-Response Relationship, Drug , Humans , Molecular Structure , Structure-Activity Relationship , Thiazoles/analysis , Thiazoles/chemistry
2.
Bioorg Med Chem Lett ; 24(22): 5265-7, 2014 Nov 15.
Article in English | MEDLINE | ID: mdl-25305688

ABSTRACT

Retinoic acid receptor-related orphan nuclear receptor gamma t (RORγt) is a key transcription factor for the development of Th17 cells. Inhibiting RORγt activity is thought to be beneficial in targeting a variety of inflammatory and autoimmune disorders. Recently N-(5-(arylcarbonyl)thiazol-2-yl)amides were described as RORγt antagonists with in vivo efficacy in experimental autoimmune encephalomyelitis (EAE) and collagen-induced arthritis (CIA) via oral administration. So far no selective small molecule ligands have been revealed for RORß. We show, that one compound of this class, namely N-[5-(2-chloro-benzoyl)-4-(3-chlorophenyl)-thiazol-2-yl]-2-(4-ethanesulfonyl-phenyl)-acetamide (4) is a potent dual inverse agonist towards RORγt and RORß devoid of activity to 18 other human nuclear receptors and thus can serve as chemical probe to deepen our understanding about RORß and its biology.


Subject(s)
Benzeneacetamides/chemistry , Nuclear Receptor Subfamily 1, Group F, Member 2/agonists , Nuclear Receptor Subfamily 1, Group F, Member 3/agonists , Thiazoles/chemistry , Tretinoin/chemistry , Benzeneacetamides/metabolism , Drug Inverse Agonism , Fluorescence Resonance Energy Transfer , Humans , Ligands , Nuclear Receptor Subfamily 1, Group F, Member 2/metabolism , Nuclear Receptor Subfamily 1, Group F, Member 3/metabolism , Protein Binding , Th17 Cells/immunology , Th17 Cells/metabolism , Thiazoles/metabolism , Tretinoin/metabolism
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