2. Academic Validation
  3. 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

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

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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