RORγ antagonists and inverse agonists: a patent review

  title={ROR$\gamma$ antagonists and inverse agonists: a patent review},
  author={Sarah M Bronner and Jason R. Zbieg and James J. Crawford},
  journal={Expert Opinion on Therapeutic Patents},
  pages={101 - 112}
ABSTRACT Introduction: The transcription factor RORγ plays a critical role in the expression of pro-inflammatory cytokine interleukin IL-17 and is therefore an attractive target for the treatment of inflammatory diseases. Interest in this molecular target has been heightened by the advancement of orally and topically administered RORγ modulators into clinical trials. Areas covered: The present review seeks to summarize published patent applications from assignee companies that have disclosed… 
Identification and biological evaluation of thiazole-based inverse agonists of RORγt.
Retinoic acid-related orphan receptor gamma t (RORγt) inverse agonists/antagonists for the treatment of inflammatory diseases – where are we presently?
  • C. Gege
  • Medicine
    Expert opinion on drug discovery
  • 2021
This review summarizes the evolution of the chemical matter for all 16 pharmaceutical companies, who develop(ed) a clinical-stage RIAs (until March 2021) and structure proposals for some clinical stage RIAs are presented and the outcome of the clinical trials is discussed.
Retinoic acid receptor-related orphan receptor gamma-t (RORγt) inhibitors in clinical development for the treatment of autoimmune diseases: a patent review (2016-present)
This article reviews the progress of RORγt inhibitors (antagonists and inverse agonists) that are active in clinical development based on an analysis of the related patents published by the corresponding companies in the period of January 2016 through May 2019.
Optimization and biological evaluation of thiazole-bis-amide inverse agonists of RORγt.
Inhibition of Interleukin-23–Mediated Inflammation with a Novel Small Molecule Inverse Agonist of RORγt
A novel small molecule inverse agonist of retinoid acid–related orphan receptor (ROR) γt is reported on and its efficacy in preclinical models of psoriasis and arthritis is shown, suggesting small molecules inverse agonists of RORγt could be efficacious in human IL-17–related diseases.
Combating Autoimmune Diseases With Retinoic Acid Receptor-Related Orphan Receptor-γ (RORγ or RORc) Inhibitors: Hits and Misses.
This review briefly summarizes the RORc inhibitors disclosed in the literature and discusses the progress made by these inhibitors in combating autoimmune diseases.
Identification of novel quinazolinedione derivatives as RORγt inverse agonist.
Discovery of Retinoic Acid-Related Orphan Receptor γt Inverse Agonists via Docking and Negative Image-Based Screening
The fact that the verified hits represent four different cores highlights the structural diversity of the RORγt inverse agonism and the ability of the applied screening methodologies to facilitate much-desired scaffold hopping for drug design.
Structural States of RORγt: X‐ray Elucidation of Molecular Mechanisms and Binding Interactions for Natural and Synthetic Compounds
Eight new X‐ray crystal structures for different classes of natural and synthetic compounds are reported, including examples selected from the patent literature, and new mechanistic insights should prove useful for the design and optimization of further RORγt modulators are reported.
(Inverse) Agonists of Retinoic Acid-Related Orphan Receptor γ: Regulation of Immune Responses, Inflammation, and Autoimmune Disease.
Changes in cholesterol biosynthesis and metabolism can have a significant impact on the generation of oxysterol RORγ ligands and, consequently, can control R ORγt activity and inflammation.


Retinoid-related orphan receptor gamma t (RORγt) inhibitors from Vitae Pharmaceuticals (WO2015116904) and structure proposal for their Phase I candidate VTP-43742
  • C. Gege
  • Biology
    Expert opinion on therapeutic patents
  • 2016
The potential elucidation of the chemical structure of clinical candidate VTP-43742 is described, combining information from Vitae’s patent applications and trustworthy online information.
Development of a Topical Treatment for Psoriasis Targeting RORγ: From Bench to Skin
A progressive series of assays are described to demonstrate the potential clinical value of a novel RORγ inverse agonist small molecule with high potency and selectivity, which will enter clinical trials in late 2015 for psoriasis patients.
ROR nuclear receptors: structures, related diseases, and drug discovery
The structural basis, disease relevance, strategies for ligand identification, and current status of development of therapeutic ligands for RORs are reviewed.
Therapeutic Targeting of IL-17 and IL-23 Cytokines in Immune-Mediated Diseases.
Therapeutic agents targeting interleukin-23/-17 and anti-IL-12/-23 regimens appear particularly effective in psoriasis, with promising results in spondyloarthropathies also emerging.
ROR inverse agonist suppresses insulitis and prevents hyperglycemia in a mouse model of type 1 diabetes.
It is suggested that TH17 cells may have a pathological role in the development of type 1 diabetes, and use of ROR-specific synthetic ligands targeting this cell type may prove utility as a novel treatment for type 1abetes.
Modulators of the nuclear receptor retinoic acid receptor-related orphan receptor-γ (RORγ or RORc).
The biology and the underlying structural biology of Rorc are discussed, and the RORc modulators disclosed in the scientific and patent literature are summarized.
Antiobesity Effect of a Small Molecule Repressor of RORγ
Results suggest that pharmacological repression of RORγ may represent a strategy for treatment of obesity by increasing thermogenesis and fatty acid oxidation, while inhibition of hormone-sensitive lipase activity results in a reduction of serum free fatty acids, leading to improved peripheral insulin sensitivity.
Targeting Th17 cells in autoimmune diseases.