Novel, Brain-Permeable, Cross-Species Benzothiazole Inhibitors of Microsomal Prostaglandin E Synthase-1 (mPGES-1) Dampen Neuroinflammation In Vitro and In Vivo

• DOI: 10.1021/acsptsci.2c00241
• Publication Date: 2023-03-21T17:50:26Z
• Authors: Madison N. Sluter; Rajib Bhuniya; Xinrui Yuan; Andhavaram Ramaraju; Yu Chen; Ying Yu; Keyur R. Parmar; Zaid H. Temrikar; Ashish Srivastava; Bernd Meibohm; Jianxiong Jiang; Chao-Yie Yang
• Keywords: Proinflammatory cytokine

Microsomal prostaglandin E synthase-1 (mPGES-1) is an inducible enzyme of the cyclooxygenase (COX) cascade that generates E2 (PGE2) during inflammatory conditions. PGE2 known to be a potent immune signaling molecule mediates both peripheral and central inflammations. Inhibition mPGES-1, rather than COX, may overcome cardiovascular side effects associated with long-term COX inhibition by providing more specific strategy target inflammation. However, mPGES-1 inhibitor development hampered large differences in cross-species activity due structural between human murine mPGES-1. Here, we report our thiazole-based inhibitors, compounds 11 (UT-11) 19 derived from two novel scaffolds, were able suppress production (SK-N-AS) (BV2) cells. The IC50 values inhibiting cells 0.10 2.00 μM for UT-11 0.43 1.55 compound 19, respectively. Based on vitro vivo pharmacokinetic data, selected evaluation lipopolysaccharide (LPS)-induced inflammation model. We found significantly suppressed proinflammatory cytokines chemokines hippocampus but not kidney. Taken together, demonstrated potential treating neuroinflammatory conditions, including epilepsy stroke, warrant further optimization.