Discovery of novel triazine derivatives as potent retinoic acid receptor-related orphan receptor γt (RORγt) inverse agonists

Lixue Lu; Song Chen; Mingcheng Yu; Ronghui Zhou; Siqi Guo; Ji-An Chen; Haojie Wang; Shijie Chen; Cheng Luo; Qiong Xie; Yonghui Wang

doi:10.1016/j.ejmech.2023.115424

Discovery of novel triazine derivatives as potent retinoic acid receptor-related orphan receptor γt (RORγt) inverse agonists

Eur J Med Chem. 2023 Aug 5:256:115424. doi: 10.1016/j.ejmech.2023.115424. Epub 2023 Apr 29.

Authors

Lixue Lu¹, Song Chen¹, Mingcheng Yu¹, Ronghui Zhou¹, Siqi Guo², Ji-An Chen¹, Haojie Wang¹, Shijie Chen², Cheng Luo², Qiong Xie³, Yonghui Wang⁴

Affiliations

¹ Department of Medicinal Chemistry, School of Pharmacy, Fudan University, 826 Zhangheng Road, Shanghai, 201203, China.
² Drug Discovery and Design Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai, 201203, China.
³ Department of Medicinal Chemistry, School of Pharmacy, Fudan University, 826 Zhangheng Road, Shanghai, 201203, China; Fudan Zhangjiang Institute, Shanghai, 201203, China. Electronic address: qxie@fudan.edu.cn.
⁴ Department of Medicinal Chemistry, School of Pharmacy, Fudan University, 826 Zhangheng Road, Shanghai, 201203, China. Electronic address: yonghuiwang@fudan.edu.cn.

PMID: 37167779
DOI: 10.1016/j.ejmech.2023.115424

Abstract

Retinoic Acid Receptor-Related Orphan Receptor γt (RORγt) has been exploited as a promising target for the new small molecule therapeutics to treat inflammatory and autoimmune diseases via modulating the interleukin-17 (IL-17) production by T helper 17 (Th17) cells. Herein, we reported a series of triazine-based derivatives as novel RORγt inverse agonists. By screening of our in-house compound library, the hit compound 1 was identified with weak RORγt inhibitory activity. Subsequently, we engineered detailed structural modifications to explore the structure-activity relationships (SARs) of triazines derivatives, which led to discovery of a number of potent RORγt inverse agonists with IC₅₀ values in the range of 7 nM-50 nM in RORγt dual FRET assay. Among them, compound 14g displayed potent RORγt inverse agonistic activity with an IC₅₀ value of 22.9 nM in dual FRET assay. In a cell-based reporter gene assay, compound 14g showed an IC₅₀ value of 0.428 μM and maximum inhibition rate of 108.9%. Compound 14g also exhibited good metabolic stability and a decent pharmacokinetic profile with a low clearance (CL = 0.229 L/h/kg) and a reasonable oral exposure (AUC_0-Last = 5058 ng/mL*h). Most importantly, 14g alleviated the severity of imiquimod-induced psoriasis in mice. Taken together, triazine-based derivatives represent a new chemical class of RORγt inverse agonists as potential therapeutic agents against autoimmune diseases.

Keywords: Autoimmune diseases; Inverse agonist; Psoriasis; RORγt; Triazines.

MeSH terms

Animals
Autoimmune Diseases* / drug therapy
Drug Inverse Agonism
Mice
Nuclear Receptor Subfamily 1, Group F, Member 3 / agonists
Receptors, Retinoic Acid* / agonists
Structure-Activity Relationship
Triazines / pharmacology
Triazines / therapeutic use

Substances

Receptors, Retinoic Acid
Nuclear Receptor Subfamily 1, Group F, Member 3
Triazines