Novel potent benzimidazole-based microsomal prostaglandin E2 synthase-1 (mPGES-1) inhibitors derived from BRP-201 that also inhibit leukotriene C4 synthase

Ergül A. G., Maz T. G., Kretzer C., Olğaç A., Jordan P. M., Çalışkan B., ...More

European Journal of Medicinal Chemistry, vol.231, 2022 (SCI-Expanded) identifier identifier identifier

  • Publication Type: Article / Article
  • Volume: 231
  • Publication Date: 2022
  • Doi Number: 10.1016/j.ejmech.2022.114167
  • Journal Name: European Journal of Medicinal Chemistry
  • Journal Indexes: Science Citation Index Expanded (SCI-EXPANDED), Scopus, Academic Search Premier, BIOSIS, CAB Abstracts, Chimica, EMBASE, MEDLINE, Veterinary Science Database
  • Keywords: mPGES-1, Leukotriene, Benzimidazole, Oxadiazolethione, Benzyloxy, PGE(2), ACCURATE DOCKING, BIOSYNTHESIS, 5-LIPOXYGENASE, IDENTIFICATION, INFLAMMATION, DERIVATIVES, THERAPY, DESIGN, GLIDE, ACIDS
  • Gazi University Affiliated: Yes

Abstract

© 2022 Elsevier Masson SASMicrosomal prostaglandin E2 synthase-1 (mPGES-1) is recognized as a promising therapeutic target for next-generation anti-inflammatory drugs to treat inflammatory diseases. In this study, we report the identification of new, potent and selective inhibitors of human mPGES-1 such as compounds 10, 31 and 49 with IC50 of 0.03–0.09 μM in a cell-free assay of PGE2 production. Compound 10 and 49 also inhibited leukotriene C4 synthase (LTC4S) at sub-μM concentrations (IC50 = 0.7 and 0.4 μM, respectively), affording compounds dually targeting inflammatory PGE2 and cysteinyl leukotriene (cys-LT) biosynthesis. However, compound 31 showed substantial selectivity towards mPGES-1 (IC50 = 0.03 μM) with a decreased inhibitory activity on LTC4S (IC50 = 2.8 μM), and also on other related targets such as FLAP and 5-LO. These oxadiazole thione-benzimidazole derivatives warrant further exploration of new and alternative analogs that may lead to the identification of novel derivatives with potent anti-inflammatory properties.