RORγt (Retinoic acid-related Orphan Receptor γ thymus) is a nuclear receptor which is expressed in immune cells such as Th17 and γδ T cells. It is identical in sequence to RORγ with the exception of a few missing amino acids at the N-terminus of the protein. RORγt is a key player in the IL-17 pathway and is involved in the synthesis of pro-inflammatory cytokines such as IL-17A, IL-17F and IL-22. It is also implicated in the differentiation of naive T cells into Th17 cells where both RORα and RORγ are highly expressed. Anti IL-17 antibodies such as secukinumab have shown robust efficacy in the treatment of psoriasis and psoriatic arthritis. A small molecule RORγt inverse agonist would, in theory, have an advantage over a targeted antibody by blocking the Th17/IL-17 cascade upstream at two different stages (differentiation and effector function). Not surprisingly, the therapeutic potential of RORγt has drawn the attention of numerous research groups. Here we report on the optimization of a series of (8-quinolyloxymethyl)benzamide derivatives with the help of a co-crystal structure of one derivative in RORγ LBD (Ligand Binding Domain). The synthesis of these derivatives, their structure activity relationship (SAR) and in vitro biological activity is described herein. The compounds were first screened in a transactivation assay using a chimeric receptor Gal4 DNA-binding domain (DBD)-human RORγ LBD transiently transfected in COS-7 cells. The best derivatives were then evaluated in an IL-17A secretion inhibition assay in human Th17 cells. Finally the selectivity vs the other ROR isoforms was evaluated in a co-activator recruitment assay using the AlphaScreenTM technology. The most interesting derivatives were tested in vivo in a mechanistic model in mouse, where they reduced IL-17 cytokine production following immune challenge. One compound also proved to be active in a multiple sclerosis model (EAE) where it reduced the disease score.

Optimization of (8-quinolyloxymethyl)benzamide derivatives as potent and selective RORγ inhibitors

2019 Fall National Meeting

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