2. Academic Validation
  3. Discovery and Optimization of N-Acyl-6-sulfonamide-tetrahydroquinoline Derivatives as Novel Non-Steroidal Selective Glucocorticoid Receptor Modulators

Discovery and Optimization of N-Acyl-6-sulfonamide-tetrahydroquinoline Derivatives as Novel Non-Steroidal Selective Glucocorticoid Receptor Modulators

  • J Med Chem. 2022 Nov 18. doi: 10.1021/acs.jmedchem.2c01082.
Dan Li 1,  Xiaodong Bao 2,  Jinping Pang 1,  Xueping Hu 3,  Longling Wang 4,  Jiajia Wang 4,  Zhaoxu Yang 4,  Lei Xu 5,  Siyu Wang 1,  Qinjie Weng 4,  Sunliang Cui 2,  Tingjun Hou 1 6
Affiliations

Affiliations

  • 1 Innovation Institute for Artificial Intelligence in Medicine of Zhejiang University, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, Zhejiang, China.
  • 2 Institute of Drug Discovery and Design, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, Zhejiang, China.
  • 3 Institute of Molecular Sciences and Engineering, Institute of Frontier and Interdisciplinary Science, Shandong University, Qingdao 266237, Shandong, China.
  • 4 Center for Drug Safety Evaluation and Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, Zhejiang, China.
  • 5 Institute of Bioinformatics and Medical Engineering, School of Electrical and Information Engineering, Jiangsu University of Technology, Changzhou 213001, Jiangsu, China.
  • 6 State Key Lab of CAD&CG, Zhejiang University, Hangzhou 310058, Zhejiang, China.
PMID: 36399795 DOI: 10.1021/acs.jmedchem.2c01082
Abstract

Selective Glucocorticoid Receptor modulators (SGRMs), which can dissociate the transactivation from the transrepression of the Glucocorticoid Receptor (GR), are regarded as very promising therapeutics for inflammatory and autoimmune diseases. We previously discovered a SGRM HP-19 based on the passive antagonistic conformation of GR and bioassays. In this study, we further analyzed the dynamic changes of the passive antagonistic state upon the binding of HP-19 and designed and synthesized 62 N-acyl-6-sulfonamide-tetrahydroquinoline derivatives by structural optimization of HP-19. Therein, compound B53 exhibits the best transrepression activity (IC50 NF-κB = 0.009 ± 0.001 μM) comparable with dexamethasone (IC50 NF-κB = 0.005 ± 0.001 μM) and no transactivation activity. B53 can efficiently reduce the expression of inflammatory factors IL-6, IL-1β, TNF-α, and so on and makes a milder adverse effect and is highly specific to GR. Furthermore, B53 is able to significantly relieve dermatitis on a mouse model via oral drug intervention.

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