Structure-Based Design and Optimization Lead to the Identification of a Novel Potent sEH Inhibitor with PPARγ Partial Agonist Activity against Inflammatory and Metabolic-Related Diseases

  • J Med Chem. 2025 Apr 24;68(8):8729-8767. doi: 10.1021/acs.jmedchem.5c00402.
Ruolin Cao  1 ,  Maoying Zhang  1 ,  Minggang Qi  1 ,  Zhen Zhang  1 ,  Christophe Morisseau  2 ,  Chunwei Zhou  3 ,  Tianqi Sun  4 ,  Junning Zhuang  1 ,  Lu Chen  1 ,  Cheng Xu  4 ,  Zhongbo Liu  5 ,  Bruce D Hammock  2 ,  Guoliang Chen  1
Affiliations
  • 1. Key Laboratory of Structure-Based Drug Design & Discovery of Ministry of Education, School of Pharmaceutical Engineering, Shenyang Pharmaceutical University, Shenyang 110016, PR China.
  • 2. Department of Entomology and Nematology and UC Davis Comprehensive Cancer Center, University of California Davis, Davis California 95616, United States.
  • 3. Shimadzu Enterprise Management (China) Co., Ltd, Shenyang 110016, People's Republic of China.
  • 4. Life Science and Biology Pharmacy College, Shenyang Pharmaceutical University, Shenyang 110016, People's Republic of China.
  • 5. School of Pharmacy, Shenyang Pharmaceutical University, Shenyang 110016, People's Republic of China.
PMID: 40186327 DOI: 10.1021/acs.jmedchem.5c00402
Abstract

The peroxisome proliferator-activated receptor-γ (PPARγ) serves as a pivotal regulator of lipid balance, adipogenesis, and inflammatory processes. PPARγ full agonists display strong curative effects but also serious adverse effects. Here, we found a novel 4-(cyclohexyloxy)phenyl acetate scaffold with partial PPARγ Agonist activity, and its structure-activity relationship was studied. We also describe the structure-guided lead optimization of orally bioavailable SP-C01 as a dual modulator of soluble Epoxide Hydrolase (sEH) and partial PPARγ, which can inhibit Ser273 phosphorylation. In mice, oral administration of SP-C01 at a dose of 5 g/kg resulted in excellent safety; a significant reduction in the negative consequences of lipid accumulation and water-sodium retention; and no gastrointestinal adverse effects, weight gain, or cardiotoxicity. In addition, SP-C01 has shown a better effect than pioglitazone (Pio.) in type 2 diabetes and nonalcoholic steatohepatitis. Additionally, SP-C01 has demonstrated potent anti-inflammatory and analgesic properties in models of both neuropathic and inflammatory pain.

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