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Structure–activity relationship studies of trisubstituted isoxazoles as selective allosteric ligands for the retinoic-acid-receptor-related orphan receptor γt

DOI: 10.1021/acs.jmedchem.1c00475 DOI Help

Authors: Femke A. Meijer (Technische Universiteit Eindhoven) , Annet O. W. M. Saris (Technische Universiteit Eindhoven) , Richard G. Doveston , Guido J. M. Oerlemans (Technische Universiteit Eindhoven) , Rens M. J. M. De Vries (Technische Universiteit Eindhoven) , Bente A. Somsen (Technische Universiteit Eindhoven) , Anke Unger (Lead Discovery Center GmbH) , Bert Klebl (Lead Discovery Center GmbH) , Christian Ottmann (Technische Universiteit Eindhoven) , Peter J. Cossar (Technische Universiteit Eindhoven) , Luc Brunsveld (Technische Universiteit Eindhoven)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Journal Of Medicinal Chemistry

State: Published (Approved)
Published: May 2021
Diamond Proposal Number(s): 27960

Open Access Open Access

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.

Journal Keywords: Agonistsl Ligands; Pyrroles; Substituents; Assays

Subject Areas: Biology and Bio-materials, Chemistry, Medicine

Instruments: I04-Macromolecular Crystallography

Other Facilities: P11 at PETRA III; ID30B at ESRF

Added On: 24/05/2021 09:47


Discipline Tags:

Non-Communicable Diseases Autoimmune Diseases Health & Wellbeing Biochemistry Chemistry Structural biology Organic Chemistry Drug Discovery Life Sciences & Biotech

Technical Tags:

Diffraction Macromolecular Crystallography (MX)