Structure-Activity Relationship Studies of Trisubstituted Isoxazoles as Selective Allosteric Ligands for the Retinoic-Acid-Receptor-Related Orphan Receptor γt

Femke A. Meijer, Annet O.W.M. Saris, Richard G. Doveston, Guido J.M. Oerlemans, Rens M.J.M. de Vries, Bente A. Somsen, Anke Unger, Bert Klebl, Christian Ottmann, Peter J. Cossar, Luc Brunsveld (Corresponding author)

Research output: Contribution to journalArticleAcademicpeer-review

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Abstract

The inhibition of the nuclear receptor retinoic-acid-receptor-related orphan receptor γt (RORγt) is a promising strategy in the treatment of autoimmune diseases. RORγt features an allosteric binding site within its ligand-binding domain that provides an opportunity to overcome drawbacks associated with orthosteric modulators. Recently, trisubstituted isoxazoles were identified as a novel class of allosteric RORγt inverse agonists. This chemotype offers new opportunities for optimization into selective and efficacious allosteric drug-like molecules. Here, we explore the structure-activity relationship profile of the isoxazole series utilizing a combination of structure-based design, X-ray crystallography, and biochemical assays. The initial lead isoxazole (FM26) was optimized, resulting in compounds with a ∼10-fold increase in potency (low nM), significant cellular activity, promising pharmacokinetic properties, and a good selectivity profile over the peroxisome-proliferated-activated receptor γ and the farnesoid X receptor. We envisage that this work will serve as a platform for the accelerated development of isoxazoles and other novel chemotypes for the effective allosteric targeting of RORγt.

Original languageEnglish
Pages (from-to)9238–9258
Number of pages21
JournalJournal of Medicinal Chemistry
Volume64
Issue number13
Early online date19 May 2021
DOIs
Publication statusPublished - 8 Jul 2021

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