Discovery of a novel RORγ antagonist with skin-restricted exposure for topical treatment of mild to moderate psoriasis.

ABSTRACT: Clinical success of IL-17/IL-23 pathway biologics for the treatment of moderate to severe psoriasis suggests that targeting RORγt, a master regulator for the proliferation and function of Th17 cells, could be an effective alternative. However, oral RORγ antagonists (VTP43742, TAK828) with high systemic exposure showed toxicity in phase I/II clinical trials and terminated development. To alleviate the potential safety concerns, identifying compounds with skin-restricted exposure amenable for topical use is of great interest. Systematic structure activity relationship study and multi-parameter optimization led to the discovery of a novel RORγ antagonist (SHR168442) with desired properties for a topical drug. It suppressed the transcription of IL-17 gene, leading to reduction of IL-17 cytokin

SUBMITTER: Liu S 

PROVIDER: S-EPMC8080595 | biostudies-literature | 2021 Apr

REPOSITORIES: biostudies-literature