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

Autor: Sluter MN; Departments of Pharmaceutical Sciences, College of Pharmacy, University of Tennessee Health Science Center, Memphis, Tennessee 38163, United States.; College of Graduate Health Sciences, University of Tennessee Health Science Center, Memphis, Tennessee 38163, United States., Bhuniya R; Departments of Pharmaceutical Sciences, College of Pharmacy, University of Tennessee Health Science Center, Memphis, Tennessee 38163, United States., Yuan X; Departments of Pharmaceutical Sciences, College of Pharmacy, University of Tennessee Health Science Center, Memphis, Tennessee 38163, United States., Ramaraju A; Departments of Pharmaceutical Sciences, College of Pharmacy, University of Tennessee Health Science Center, Memphis, Tennessee 38163, United States., Chen Y; Departments of Pharmaceutical Sciences, College of Pharmacy, University of Tennessee Health Science Center, Memphis, Tennessee 38163, United States., Yu Y; Departments of Pharmaceutical Sciences, College of Pharmacy, University of Tennessee Health Science Center, Memphis, Tennessee 38163, United States., Parmar KR; Departments of Pharmaceutical Sciences, College of Pharmacy, University of Tennessee Health Science Center, Memphis, Tennessee 38163, United States., Temrikar ZH; Departments of Pharmaceutical Sciences, College of Pharmacy, University of Tennessee Health Science Center, Memphis, Tennessee 38163, United States., Srivastava A; Departments of Pharmaceutical Sciences, College of Pharmacy, University of Tennessee Health Science Center, Memphis, Tennessee 38163, United States., Meibohm B; Departments of Pharmaceutical Sciences, College of Pharmacy, University of Tennessee Health Science Center, Memphis, Tennessee 38163, United States., Jiang J; Departments of Pharmaceutical Sciences, College of Pharmacy, University of Tennessee Health Science Center, Memphis, Tennessee 38163, United States., Yang CY; Departments of Pharmaceutical Sciences, College of Pharmacy, University of Tennessee Health Science Center, Memphis, Tennessee 38163, United States.
Jazyk: angličtina
Zdroj: ACS pharmacology & translational science [ACS Pharmacol Transl Sci] 2023 Mar 21; Vol. 6 (4), pp. 587-599. Date of Electronic Publication: 2023 Mar 21 (Print Publication: 2023).
DOI: 10.1021/acsptsci.2c00241
Abstrakt: Microsomal prostaglandin E synthase-1 (mPGES-1) is an inducible enzyme of the cyclooxygenase (COX) cascade that generates prostaglandin E2 (PGE 2 ) during inflammatory conditions. PGE 2 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 PGE 2 production in human (SK-N-AS) and murine (BV2) cells. The IC 50 values of inhibiting PGE 2 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.
Competing Interests: The authors declare no competing financial interest.
(© 2023 American Chemical Society.)
Databáze: MEDLINE
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