Discovery of 2-((2-chloro-6-fluorophenyl)amino)-N-(3-fluoro-5-(trifluoromethyl)phenyl)-1-methyl-7,8-dihydro-1H-[1,4]dioxino[2′,3′:3,4]benzo[1,2-d]imidazole-5-carboxamide as potent, selective and efficacious microsomal prostaglandin E₂ synthase-1 (mPGES-1) inhibitor

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• 作者：Nagarajan Muthukaman^a ; Sanjay Deshmukh^a ; Neelam Sarode^a ; Shital Tondlekar^a ; Macchindra Tambe^a ; Dnyandeo Pisal^a ; Mahamadhanif Shaikh^a ; Vidya G. Kattige^b ; Srinivasa Honnegowda^b ; Vikas Karande^b ; Abhay Kulkarni^b ; Satyawan B. Jadhav^c ; Mahamad Yunnus A. Mahat^c ; Girish S. Gudi^c ; Neelima Khairatkar-Joshi^b ; Laxmikant A. Gharat^a ; ^{Laxmikant.gharat@glenmarkpharma.com}
• 关键词：Rheumatoid arthritis ; Benzimidazole ; mPGES-1 inhibitor ; PGE2 ; CSF concentration ; Scaffold hopping
• 刊名：Bioorganic & Medicinal Chemistry Letters
• 出版年：2016
• 出版时间：15 December 2016
• 年：2016
• 卷：26
• 期：24
• 页码：5977-5984
• 全文大小：1187 K
• 卷排序：26

文摘

The discovery and SAR of potent, selective dioxane-fused tricyclic benz[d]imidazole derivatives as mPGES-1 inhibitor are herein described. Various amide modifications in this series afforded many potent mPGES-1 inhibitors, of which 17d proved to be suitable for further profiling in vivo. Compound 17d {2-((2-chloro-6-fluorophenyl)amino)-N-(3-fluoro-5-(trifluoromethyl)phenyl)-1-methyl-7,8-dihydro-1H-[1,4]dioxino[2′,3′:3,4]benzo[1,2-d]imidazole-5-carboxamide} exhibited excellent mPGES-1 enzyme (IC50: 8 nM), cell (A549 IC50: 16.24 nM) and human whole blood potency (IC50: 249.9 nM). In rodent species, 17d strongly inhibited guinea pig mPGES-1 (IC50: 10.79 nM), but not the rat and mouse enzyme. Furthermore 17d displayed excellent in vitro selectivity over mPGES-2, cPGES, COX-enzymes (COX-1, 2), selectivity against other prostanoid synthases, favorable hERG and CEREP panel profile. Likewise, our lead 17d demonstrated good oral pharmacokinetic profiles and good CNS B/P ratio in rat and guinea pig. Lead 17d also unveiled good efficacy in LPS-induced thermal hyperalgesia pain model with ED50 of 36.7 mg/kg, respectively.