Structure-Activity Relationship Studies of 2,4,5-Trisubstituted Pyrimidine Derivatives Leading to the Identification of a Novel and Potent Sirtuin 5 Inhibitor against Sepsis-Associated Acute Kidney Injury

  • J Med Chem. 2023 Aug 24;66(16):11517-11535. doi: 10.1021/acs.jmedchem.3c01031.
Luohe Mou  1 ,  Lina Yang  2 ,  Shuyan Hou  3 ,  Bo Wang  2 ,  Xinyue Wang  3 ,  Lei Hu  1 ,  Jianlin Deng  1 ,  Jiayu Liu  1 ,  Xi Chen  1 ,  Yingying Jiang  1 ,  Weifeng Zhang  1 ,  Pengcheng Lei  1 ,  Lijiao Wang  1 ,  Rong Li  1 ,  Ping Fu  2 ,  Guo-Bo Li  3 ,  Liang Ma  2 ,  Lingling Yang  1
Affiliations
  • 1. College of Food and Bioengineering, Xihua University, Chengdu 610039, China.
  • 2. Division of Nephrology, Kidney Research Institute, West China Hospital of Sichuan University, Chengdu 610041, China.
  • 3. Key Laboratory of Drug Targeting and Drug Delivery System of Ministry of Education, West China School of Pharmacy, Sichuan University, Chengdu 610041, China.
PMID: 37556731 DOI: 10.1021/acs.jmedchem.3c01031
Abstract

Sepsis-associated acute kidney injury (AKI) is a serious clinical problem without effective drugs. Inhibition of Sirtuin 5 (SIRT5) has been confirmed to protect against AKI, suggesting that SIRT5 inhibitors might be a promising therapeutic approach for AKI. Herein, structural optimization was performed on our previous compound 1 (IC50 = 3.0 μM), and a series of 2,4,5-trisubstituted pyrimidine derivatives have been synthesized. The structure-activity relationship (SAR) analysis led to the discovery of three nanomolar level SIRT5 inhibitors, of which the most potent compound 58 (IC50 = 310 nM) was demonstrated to be a substrate-competitive and selective inhibitor. Importantly, 58 significantly alleviated kidney dysfunction and pathological injury in both lipopolysaccharide (LPS)- and cecal ligation/perforation (CLP)-induced septic AKI mice. Further studies revealed that 58 regulated protein succinylation and the release of proinflammatory cytokines in the kidneys of septic AKI mice. Collectively, these results highlighted that targeting SIRT5 has a therapeutic potential against septic AKI.

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