2. Academic Validation
  3. A piperidinyl indole derivative, potential complement factor B inhibitor, plays a renoprotective role in diabetic nephropathy

A piperidinyl indole derivative, potential complement factor B inhibitor, plays a renoprotective role in diabetic nephropathy

  • Diabet Med. 2025 Aug;42(8):e70092. doi: 10.1111/dme.70092.
Zi-Han Li 1 2 3 4 5 6,  Zi-Jun Sun 1 2 3 4 5 6 7,  Dong-Yuan Chang 1 2 3 4 5 6,  Ming-Hui Zhao 1 2 3 4 5 6,  Sydney C W Tang 8,  Min Chen 1 2 3 4 5 6
Affiliations

Affiliations

  • 1 Renal Division, Department of Medicine, Peking University First Hospital, Beijing, China.
  • 2 Peking University Institute of Nephrology, Beijing, China.
  • 3 Key Laboratory of Renal Disease, Ministry of Health of China, Beijing, China.
  • 4 Key Laboratory of Chronic Kidney Disease Prevention and Treatment (Peking University), Ministry of Education, Beijing, China.
  • 5 Department of Nephrology, Peking University First Hospital; State Key Laboratory of Vascular Homeostasis and Remodeling, Peking University, Beijing, China.
  • 6 Research Units of Diagnosis and Treatment of Immune-Mediated Kidney Diseases, Chinese Academy of Medical Sciences, Beijing, China.
  • 7 Shandong Provincial Hospital Affiliated to Shandong First Hospital Medical University, Jinan, Shandong, China.
  • 8 Division of Nephrology, Department of Medicine, Queen Mary Hospital, The University of Hong Kong, Hong Kong, China.
PMID: 40518691 DOI: 10.1111/dme.70092
Abstract

Aims: Diabetic nephropathy (DN) is one of the most common complications of diabetes mellitus (DM) and the main cause of end-stage kidney disease (ESKD) worldwide. The pathogenesis of DN is complex, and cumulating evidence demonstrated that over-activation of the Complement System is involved. Complement Factor B (CFB), a serine protease, drives the central amplification loop of the alternative pathway (AP) of the complement, making it a potential therapeutic target. In this study, we investigated the therapeutic potential of a piperidinyl indole derivative in db/db mice.

Methods: A highly potent CFB-targeting compound, (+)-4-((2S,4R)-1-((5-methoxy-7-methyl-1H-indol-4-yl) methyl)-4-methylpiperidin-2-yl) benzoic acid (hereafter referred as the "compound"), was orally administered to the db/db mice model. Bioinformatics and network pharmacology analyses were applied in our research.

Results: Oral administration of the compound attenuated established DN in db/db mice, as evidenced by reduced urine albumin-to-creatine ratio (uACR), tubulointerstitial inflammation and fibrosis, and thickening of glomerular basement membrane. Besides binding to the active site of Bb, the enzyme-cleaved activated fragment of CFB, and inhibiting the activity of Complement Component 3 (C3) convertase of the AP, the compound could regulate the expression of cysteinyl aspartate specific proteinase 3 (CASP3, a key executor of renal tubular Apoptosis) and Dipeptidyl Peptidase 4 (DPP4, a pro-fibrotic driver in tubulointerstitium) by bioinformatics and network pharmacology analysis. These complementary mechanisms cooperated to inhibit the over-activation of complements and the Apoptosis/fibrosis cascade and together alleviated DN progression.

Conclusions: Our data revealed the potential therapeutic strategy of using the piperidinyl indole derivative for the treatment of DN and provided a basis for its clinical development.

Keywords

alternative pathway; complement factor B inhibitor; diabetic nephropathy; mitochondria; piperidinyl indole derivative.

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