2. Academic Validation
  3. Discovery of 1-(Hetero)aryl-β-carboline Derivatives as IDO1/TDO Dual Inhibitors with Antidepressant Activity

Discovery of 1-(Hetero)aryl-β-carboline Derivatives as IDO1/TDO Dual Inhibitors with Antidepressant Activity

  • J Med Chem. 2022 Aug 25;65(16):11214-11228. doi: 10.1021/acs.jmedchem.2c00677.
Yu Zhang 1,  Yingchun Li 2,  Xiang Chen 2,  Xuan Chen 2,  Chao Chen 3,  Li Wang 3,  Xu Dong 2,  Guoli Wang 2,  Ruxin Gu 4,  Fei Li 2,  Feng Han 1 4 5,  Dongyin Chen 1 2
Affiliations

Affiliations

  • 1 Key Laboratory of Cardiovascular & Cerebrovascular Medicine, Drug Target and Drug Discovery Center, School of Pharmacy, Nanjing Medical University, Nanjing 211166, China.
  • 2 Department of Medicinal Chemistry, School of Pharmacy, Nanjing Medical University, Nanjing 211166, China.
  • 3 Key Laboratory of Modern Toxicology of Ministry of Education, School of Public Health, Nanjing Medical University, Nanjing 211166, China.
  • 4 Institute of Brain Science, The Affiliated Brain Hospital of Nanjing Medical University, Nanjing 211166, China.
  • 5 Gusu School, Nanjing Medical University, Suzhou Municipal Hospital, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou 215002, China.
PMID: 35938398 DOI: 10.1021/acs.jmedchem.2c00677
Abstract

Depression is the leading cause of global burden of disease and disability. Abnormalities in the kynurenine pathway of tryptophan degradation have been closely linked to the pathogenesis of depression. An integrative bioinformatics analysis demonstrated that indoleamine 2,3-dioxygenase 1 (IDO1) and tryptophan 2,3-dioxygenase (TDO) are potential targets for the development of antidepressants. A series of 1-(hetero)aryl-β-carboline derivatives were designed, synthesized, and evaluated as novel IDO1/TDO dual inhibitors. Among them, compound 28 displayed potent inhibition of both IDO1 (IC50 = 3.53 μM) and TDO (IC50 = 1.15 μM) and had an acceptable safety profile and pharmacokinetic properties. Compound 28 also rescued lipopolysaccharide-induced depressive-like behavior in mice. Further studies revealed that 28 likely had unique antidepressant mechanisms involving suppressing microglial activation, lowering IDO1 expression, and reducing proinflammatory cytokine and kynurenine levels in the mouse brain. Overall, this work provides practical guidance for the development of IDO1/TDO dual inhibitors to treat inflammation-induced depression.

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