Retinoid-related orphan receptor gamma t (RORgt) is a ligand-regulated transcription factor (nuclear receptor) and is required for the development and function of multiple important pro-inflammatory lymphocyte lineages including TH17 cells. RORgt-expressing cells and the cytokines they produce have been implicated in the pathogenesis of human autoimmune diseases including Psoriasis, Crohn’s Disease, and Multiple Sclerosis. Disruption of the RORgt /TH17 pathway by genetic targeting, small molecule-mediated inhibition, or antibody-mediated neutralization of pathway cytokines (e.g. IL-23, IL-17a, IL-17f, and GMCSF) reduced or eliminated disease in numerous animal models of autoimmune pathology. In humans, biologics targeting cytokines in the RORgt pathway have demonstrated clinical efficacy. Thus, RORgt is an attractive target for small molecule therapeutic intervention. As part of an effort to develop an RORg inverse agonist for potential therapeutic use, we have investigated multiple chemical scaffolds with diverse array of features. Given the highly lipophilic ligand binding pocket of RORg, a central challenge for developing an attractive candidate is achieving both high potency and good drug-like properties. This presentation will focus on a biaryl series with a strategically positioned polar head and an oxime series with a water mediated hydrogen-bond in the lipophilic pocket. SAR and property data for two series will be discussed. Lead compounds from each series and our knowledge gained in the development of these series may be useful for future development of RORg inverse agonists.

Dealing with a highly lipophilic binding pocket: design and development of novel RORg inverse agonists with the consideration of ligand polarity and conformational diversity

249th National Meeting (2015)

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