Retinoic acid-related orphan receptor γt (RORγt) is a nuclear hormone receptor (NHR) and belongs to the RORγ family. It exists in the thymus and contributes to the differentiation of CD4+T cells into Th17 cells. This factor plays an important role in the production of the pro-inflammatory cytokine, such as IL-17, GM-CSF, IL-21, and IL-22, et al.
Psoriasis is an autoimmune disease with skin inflammation. It is a skin disease with erythematous and plaques with an overlying silvery scale. This disease relates to the IL-23/IL-17 pathway. RORγt is able to control the apoptosis of CD4+ CD8+ double-positive (DP)thymocytes. Many small-molecule inhibitors RORγt attracts attention for the treatment of autoimmune Th17-mediated inflammation.
In this article, we will introduce a small molecule inhibitor of RORγt, BMS-986251.
BMS-986251 is an orally active and selective RORγt inverse agonist with an EC50 of 12 nM for RORγt GAL4. It inhibits IL-17 with an EC50 of 24 nM in human whole blood assay. At the same time, BMS-986251 demonstrates robust efficacy in mouse acanthosis and Imiquimod-induced (HY-B0180) models (preclinical models of psoriasis).
In vivo, in a pharmacokinetic analysis in rats. BMS-986251 exhibits a T1/2 of 11 hours, a CL of 1.3 mL/min•kg, and a Vss of 1.25 L/kg for intravenous injection. Besides, it exhibits a Cmax of 4.7 μM and an AUC of 64 μM•h for oral administration.
What more, in a PK study in mice. BMS-986251 has a T1/2 of 7.7 hours, a CL of 2.7 mL/min•kg, and a Vss of 1.9 L/kg for IV in the mouse. Additionally, it shows a Cmax of 4.8 μM and an AUC of 37 μM•h for PO in the mouse.
Lastly, in C57BL/6 female mice with acanthosis. IMQ can result in reduced ear thickness. BMS-986251 can significantly reduce imiquimod (IMQ)-induced skin thickening. Furthermore, BMS-986251 displays a dose-dependent reduction of the IL-17F produced in mice.
In conclusion, as a potent and orally active RORγt inverse agonist, BMS-986251 provides the potential for the study of autoimmune disease, especially psoriasis.
Robert J. Cherney, et al. ACS Med. Chem. Lett. 2020, 11, 6, 1221–1227