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Discovery of potent and selective retinoid related orphan receptor gamma (RORγ) inverse agonists for the treatment of Th17 mediated diseases

Kavitha Nellore1, Mallesham Bejugam1, Anuradha Ramanathan1, Subhendu Mukherjee1, Anirudha Lakshminarasimhan1, Samiulla S. Dodheri1, Narasimha Rao1, Ravi Krishna Babu Damarla1, Susanta Samajdar1 and Hosahalli Subramanya1*
  • 1 Aurigene Discovery Technologies Ltd., India

Background: Th17 cells play a key pro-inflammatory role in a variety of autoimmune diseases. The nuclear hormone receptor RORγ controls the differentiation of Th17 cells and expression of IL-17.
Methods: Novel RORγ inverse agonists were designed using structure and knowledge based methods. Compounds were screened in a RORγ radio-ligand binding assay using 3H 25- Hydroxycholesterol, as well as in a cell based reporter assay to demonstrate inverse agonism. Selected compounds were screened against RORα to evaluate selectivity. Crystal structure of RORγ in complex with known inverse agonists as well as novel compounds, were solved. Th17 differentiation assay was developed using primary mouse CD4+ve T-cells to determine functional effect of the compounds. Pharmacokinetic profile in mice was determined for selected compounds.
Results: Novel hits from multiple structural classes have been identified, with IC50 in the range of 5 – 500 nM in binding assay. Compounds from the lead series demonstrated good activity (< 1 μM) in reporter assay. Co-crystal structure of novel compounds clearly showed the mode of binding. Several compounds demonstrated > 10 fold selectivity against RORα in a reporter assay. Compounds from multiple series have shown significant inhibition of IL-17 release from differentiated Th17 cells. Lead compounds have shown good pharmacokinetic properties in mice.
Conclusions: We have identified novel and structurally diverse small molecule inverse agonists of
RORγ. Selectivity against RORα and cell based activity has been demonstrated for compounds from multiple series. Relevant efficacy models have been established and profiling of lead compounds in these models in on-going.

Keywords: RORγ, Autoimmune Diseases, Th17 Cells, IL-17, Psoriasis

Conference: 15th International Congress of Immunology (ICI), Milan, Italy, 22 Aug - 27 Aug, 2013.

Presentation Type: Abstract

Topic: Immune-mediated disease pathogenesis

Citation: Nellore K, Bejugam M, Ramanathan A, Mukherjee S, Lakshminarasimhan A, Dodheri SS, Rao N, Damarla R, Samajdar S and Subramanya H (2013). Discovery of potent and selective retinoid related orphan receptor gamma (RORγ) inverse agonists for the treatment of Th17 mediated diseases. Front. Immunol. Conference Abstract: 15th International Congress of Immunology (ICI). doi: 10.3389/conf.fimmu.2013.02.00678

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Received: 13 Jun 2013; Published Online: 22 Aug 2013.

* Correspondence: Dr. Hosahalli Subramanya, Aurigene Discovery Technologies Ltd., Bangalore, India, hosahalli_s@aurigene.com