Inflammation

Cell culture, mouse, rat and dog studies identified a RORγT inverse agonist that could help treat inflammation. Chemical synthesis and screening of a subset of Pfizer Inc.’s small compound library in a HEK-cell based activity assay, followed by optimization and testing of the top hit in a human T helper type 17 (Th17) cell-based activity assay yielded an indole-benzamide analog that inhibited RORγT-dependent IL-17 production with an IC₅₀ of 9.5 nM. In mouse Th17 cells, the compound inhibited IL-17 production with an IC₅₀ of 32 nM. In a mouse model of chemical-induced skin inflammation, the compound decreased ear swelling and levels of IL-17A protein in the ear compared with vehicle. In mice, rats and dogs, a spray-dried dispersion formulation of the compound had 30%, 83% and 73% oral bioavailability, respectively. Next steps by Pfizer could include testing the spray-dried dispersion formulation in additional models of inflammation.

Takeda Pharmaceutical Co. Ltd. has TAK-828, a RORγT inverse agonist, in Phase I testing to treat Crohn disease...