Psoriasis is a common chronic inflammatory disease involving dynamic interactions between the immune system and the skin. Histologically, psoriatic lesions are characterized by epidermal hyperplasia, immune cell infiltration in the dermis and hypervascularization. Recently developed IL-17-targeting monoclonal antibodies have proven to be successful in reducing the disease burden of moderate-to-severe psoriasis patients . Within psoriatic lesions, IL-17 can be produced by several cell types, including Th17 cells, γδ T cells, CD8 T cells, innate lymphoid cells (ILC3s), neutrophils and possibly mast cells. Although several transcription factors may be important, the development and maintenance of IL-17 producing cells is controlled by the nuclear receptor retinoid related orphan receptor gamma t (RORγt). RORγt is both necessary and sufficient for IL-17 expression and Th17 lineage differentiation in both humans and mice. In addition, imiquimod-induced psoriasiform-skin inflammation in mice is attenuated by RORγt gene deficiency as well as by oral treatment with RORγ small molecule inverse agonists. 
Here we describe compound A, a potent and selective inverse agonist of the human RORγ receptor specifically designed for topical administration, that markedly inhibits Th17-type cytokine production and the hallmarks of psoriasis in multiple assays systems, including (i) human and mouse cellular assays, (ii) the imiquimod mouse model, and (iii) a human skin transplant mouse model.

Topical RORγ inverse agonist alleviate preclinical models of psoriasis