Novel potent benzimidazole-based microsomal prostaglandin E2 synthase-1 (mPGES-1) inhibitors derived from BRP-201 that also inhibit leukotriene C4 synthase
European Journal of Medicinal Chemistry, cilt.231, 2022 (SCI-Expanded, Scopus)
- Yayın Türü: Makale / Tam Makale
- Cilt numarası: 231
- Basım Tarihi: 2022
- Doi Numarası: 10.1016/j.ejmech.2022.114167
- Dergi Adı: European Journal of Medicinal Chemistry
- Derginin Tarandığı İndeksler: Science Citation Index Expanded (SCI-EXPANDED), Scopus, Academic Search Premier, BIOSIS, CAB Abstracts, Chimica, EMBASE, MEDLINE, Veterinary Science Database
- Anahtar Kelimeler: mPGES-1, Leukotriene, Benzimidazole, Oxadiazolethione, Benzyloxy, PGE(2), ACCURATE DOCKING, BIOSYNTHESIS, 5-LIPOXYGENASE, IDENTIFICATION, INFLAMMATION, DERIVATIVES, THERAPY, DESIGN, GLIDE, ACIDS
- Gazi Üniversitesi Adresli: Evet
Özet
© 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.