Identification of the first inverse agonist of retinoid-related orphan receptor (ROR) with dual selectivity for RORbeta and RORgammat.

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Gege C, Schluter T, Hoffmann T

Identification of the first inverse agonist of retinoid-related orphan receptor (ROR) with dual selectivity for RORbeta and RORgammat.

Bioorg Med Chem Lett. 2014 Nov 15;24(22):5265-7. doi: 10.1016/j.bmcl.2014.09.053. Epub 2014 Sep 28.

PubMed ID

25305688 [ View in PubMed

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Abstract

Retinoic acid receptor-related orphan nuclear receptor gamma t (RORgammat) is a key transcription factor for the development of Th17 cells. Inhibiting RORgammat 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 RORgammat 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 RORbeta. 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 RORgammat and RORbeta devoid of activity to 18 other human nuclear receptors and thus can serve as chemical probe to deepen our understanding about RORbeta and its biology.