Discovery of a CYP2E1 inhibitor and its therapeutic potential in severe acute pancreatitis

Abstract

Cytochrome P450 2E1 (CYP2E1) is a key enzyme in the cytochrome P450 family, playing a crucial role in metabolizing a wide range of endogenous and exogenous compounds. It is also pivotal in the onset and progression of inflammation. Despite the demonstrated anti-inflammatory effects of existing CYP2E1 inhibitors in various animal models, their clinical application remains limited due to poor selectivity, high toxicity, degradation susceptibility, and limited in vivo solubility. Through virtual screening, synthesis, and optimization, we identified compound 10 as a favorable selective and potent CYP2E1 inhibitor, with a K_d of 7.02 μM, an IC₅₀ of 1.64 μM, and a K_i of 0.897 μM. Notably, treatment with 10 significantly reduced mortality, inflammation, and oxidative stress in mouse models of severe acute pancreatitis (SAP) induced by Caerulein combined with lipopolysaccharide (LPS) or l-Arginine. 10 significantly promoted the expression of Nrf2 in pancreatic tissues of the two SAP models; in vitro studies revealed that inactivation of Nrf2 signaling and increase of reactive oxygen species (ROS) were reversed by 10 in Caerulein-treated AR42J cells. Overall, our study identified a selective and potent small molecule CYP2E1 inhibitor 10, which may not only serve as a candidate compound for the treatment of SAP but also lay the groundwork for future drug development of anti-inflammatory agents.