Discovery of N-amido-phenylsulfonamide derivatives as novel microsomal prostaglandin E2 synthase-1 (mPGES-1) inhibitors

• Published in: Bioorganic & medicinal chemistry letters 2021-06, Vol.41, p.127992-127992, Article 127992
• Main Authors: Kim, Misong, Kim, Geuntae, Kang, Minji, Ko, Dohyeong, Nam, Yunchan, Moon, Chang Sang, Kang, Heung Mo, Shin, Ji-Sun, Werz, Oliver, Lee, Kyung-Tae, Lee, Jae Yeol
• Format: Article
• Language: English
• Subjects: Bioisosteric replacement; Inflammation; Molecular docking; mPGES-1 inhibitor; PGE2
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2021.127992

[Display omitted] Our previous research showed that N-carboxy-phenylsulfonyl hydrazide (scaffold A) could reduce LPS-stimulated PGE2 levels in RAW 264.7 macrophage cells by an inhibition of mPGES-1 enzyme. However, a number of scaffold A derivatives showed the drawbacks such as the formation of regioisomers and poor liver metabolic stability. In order to overcome these synthetic and metabolic problems, therefore, we decided to replace N-carboxy-phenylsulfonyl hydrazide (scaffold A) with N-carboxy-phenylsulfonamide (scaffold B) or N-amido-phenylsulfonamide frameworks (scaffold C) as a bioisosteric replacement. Among them, MPO-0186 (scaffold C) inhibited the production of PGE2 (IC50: 0.24 μM) in A549 cells via inhibition of mPGES-1 (IC50: 0.49 μM in a cell-free assay) and was found to be approximately 9- and 8-fold more potent than MK-886 as a reference inhibitor, respectively. A molecular docking study theoretically suggests that MPO-0186 could inhibit PGE2 production by blocking the PGH2 binding site of mPGES-1 enzyme. Furthermore, MPO-0186 demonstrated good liver metabolic stability and no significant inhibition observed in clinically relevant CYP isoforms except CYP2C19. This result provides a potential starting point for the development of selective and potent mPGES-1 inhibitor with a novel scaffold.