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

• Published in: ACS pharmacology & translational science Vol. 6; no. 4; pp. 587 - 599
• Main Authors: Sluter, Madison N., Bhuniya, Rajib, Yuan, Xinrui, Ramaraju, Andhavaram, Chen, Yu, Yu, Ying, Parmar, Keyur R., Temrikar, Zaid H., Srivastava, Ashish, Meibohm, Bernd, Jiang, Jianxiong, Yang, Chao-Yie
• Format: Journal Article
• Language: English
• Published: United States American Chemical Society 14.04.2023
• Subjects: PGE2; mPGES-1; COX-2; neuroinflammation; mPGES-1 inhibitors; cytokines; anti-inflammatory effects; chemokines
• ISSN: 2575-9108; 2575-9108
• DOI: 10.1021/acsptsci.2c00241

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