The evolution paths of some reprehensive scaffolds of RORt modulators, a perspective from medicinal chemistry

The ligand binding domain (LBD) of retinoid-related orphan nuclear receptor gamma t (ROR gamma t) has been exploited as a promising target for the new small molecule therapeutics to cure autoimmune diseases via modulating the IL-17 and IL-22 production by Th17 cells. Diverse chemical scaffolds of these small molecules have been discovered by multiple groups with methods such as high throughput screening (HTS) and virtual screening. These different scaffolds are further developed by medicinal chemists to afford lead compounds the best of which enter clinical trials. In this review, we summarize these chemical scaffolds and their evolution paths according to the groups in which they have been discovered or studied. We combine the data of the chemistry, biological assays and structural biology of each chemical scaffold, in order to afford insight to develop new RORgt modulators with higher potency, less toxicity and elucidated working mechanism. (C) 2021 Elsevier Masson SAS. All rights reserved.