Discovery of N-(2-benzyl-4-oxochroman-7-yl)-2-(5-(ethylsulfonyl) pyridin-2-yl) acetamide (b12) as a potent, selective, and orally available novel retinoic acid receptor-related orphan receptor γt inverse agonist

The nuclear receptor retinoic acid receptor-related orphan receptor gamma (ROR gamma, NR1F3, or RORc) exists in two isoforms, with one isoform (ROR gamma or RORc1) widely expressed in a variety of tissues, and the expression of the second isoform (ROR gamma t or RORc2) restricted to the thymus and cells of the immune system. ROR gamma t is a key regulator of the development and functions of T-helper 17 (Th17) cells. Clinical proof-of-concept (PoC) with small molecule inverse agonists of ROR gamma t has been achieved with VTP-43742 (Phase II) for the treatment of psoriasis, and pre-clinical PoC for this mechanism has also been established for the treatment of autoimmune diseases. A series of aryl sulfonyl derivatives as novel ROR gamma t inverse agonists were designed and synthesized based on VTP-43742. We conducted structural modifications that improved the activity profile. In pharmacodynamic (PD) studies, oral administration of compound b12 showed robust and dose-dependent inhibition of IL-6 and IL-17A cytokine expression. The ability of compound b12 to reduce the levels of IL-6 and IL-17A in vivo after oral dosing in mice, and a corresponding reduction in skin inflammation further supports the potential of small molecule ROR gamma t modulation as a therapeutic target for the treatment of inflammatory diseases.

Automated summary

The nuclear receptor ROR gamma exists in two isoforms, with one widely expressed in various tissues and the other restricted to the thymus and immune system cells. ROR gamma t, a key regulator of Th17 cell development and function, has shown potential for the treatment of psoriasis and autoimmune diseases. Structural modifications of a known ROR gamma t inverse agonist resulted in improved activity, with compound b12 demonstrating dose-dependent inhibition of IL-6 and IL-17A cytokine expression. This suggests the potential of small molecule ROR gamma t modulation as a therapeutic target for inflammatory diseases.