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

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 <b>SP-C01</b> as a dual modulator of soluble epoxide hydrolase (sEH) and partial PPARγ, which can inhibit Ser273 phosphorylation. In mice, oral administration of <b>SP-C01</b> 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, <b>SP-C01</b> has shown a better effect than pioglitazone (<b>Pio.</b>) in type 2 diabetes and nonalcoholic steatohepatitis. Additionally, <b>SP-C01</b> has demonstrated potent anti-inflammatory and analgesic properties in models of both neuropathic and inflammatory pain.