2. Academic Validation
  3. Discovery of Novel Nonsteroidal SGRMs of Sulfonamide-2-Oxo-Tetrahydroquinoline Derivatives by Carbonyl Migration

Discovery of Novel Nonsteroidal SGRMs of Sulfonamide-2-Oxo-Tetrahydroquinoline Derivatives by Carbonyl Migration

  • J Med Chem. 2026 Jan 22;69(2):1507-1529. doi: 10.1021/acs.jmedchem.5c02983.
Xiaodong Bao 1 2 3,  Yuxin Zhou 1,  Zhaoxu Yang 4,  Yongxin Zhong 3,  Xueping Hu 5,  Zhibin Li 4,  Jie Li 2,  Li Xiao 6,  Tingjun Hou 1,  Qinjie Weng 4,  Jiajia Wang 4,  Sunliang Cui 1 7,  Dan Li 1 7
Affiliations

Affiliations

  • 1 State Key Laboratory of Advanced Drug Delivery and Release Systems, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, Zhejiang, China.
  • 2 School of Medicine, Hangzhou City University, Hangzhou 310015, Zhejiang, China.
  • 3 Institute of Drug Discovery and Design, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, Zhejiang, China.
  • 4 Center for Drug Safety Evaluation and Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, Zhejiang, China.
  • 5 Institute of Molecular Sciences and Engineering, Institute of Frontier and Interdisciplinary Science, Shandong University, Qingdao 266237, Shandong, China.
  • 6 College of Life Science, Huzhou University, Huzhou 313000, Zhejiang, China.
  • 7 Jinhua Institute of Zhejiang University, Jinhua 321000, Zhejiang, China.
PMID: 41490153 DOI: 10.1021/acs.jmedchem.5c02983
Abstract

Glucocorticoids (GCs) are limited by severe side effects, driving the development of selective Glucocorticoid Receptor modulators (SGRMs) with improved therapeutic profiles. We previously development the SGRM lead B53, which suffered from poor metabolic stability. In this study, structure-guided optimization of B53 yielded 43 novel sulfonamide derivatives. Among them, D8, which contained 2-oxo-tetrahydroquinoline by carbonyl migration form B53, manifests an excellent SGRM with remarkable transrepression potency (IC50NF-κB = 0.9 nM) superior to dexamethasone (IC50 NF-κB = 5.0 nM). Besides, D8 exhibits a significantly higher specificity for GR over AR, MR, and PR and exhibited less adverse effects on Osteoprotegerin. Furthermore, D8 demonstrated improved metabolic stability and optimized binding mode within the GR LBD. In vivo, oral administration of D8 significantly alleviated dermatitis and autoimmune hepatitis in mouse models, underscoring its therapeutic potential and validating our design strategy.

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