title: Identification of furo[3', 2':3,4]naphtho[1,2-d]imidazole derivatives as orally active and selective inhibitors of microsomal prostaglandin E(2) synthase-1 (mPGES-1).
abstract: This study describes the synthesis and anti-inflammatory effects of furo[3', 2':3,4]naphtho[1,2-d] imidazole derivatives. Among these furo[3', 2':3,4]naphtho[1,2-d]imidazole derivatives, 2-(4-methoxyphenyl)furo [3', 2':3,4]naphtho[1,2-d]imidazole (12) exhibited a strong inhibitory activity against LPS-induced PGE(2) production, with an IC(50) value of 47 nM. Compound 12 is then further examined for its inhibitory effects in the protein expression of COX-2 and microsomal prostaglandin E(2) synthase-1 (mPGES-1) in Raw 264.7 cells. Our results indicate that compound 12 was capable against inhibiting LPS-induced mPGES-1 protein expression at a concentration of 1.0 μM and no inhibitory effect in COX-2 expression. The sepsis-induced PGE(2) production in rat serum decreased ~250% by the pretreatment of 12 at 10 mg/kg. These results are especially important since compound 12 exhibited good oral bioavailability (72%) and was not cytotoxic at a concentration of 10.0 μM. Therefore, compound 12 is a highly selective mPGES-1 inhibitor that can serve as a lead for the development of novel oral anti-inflammatory drug candidates.
authors.affiliation: Department of Medicinal and Applied Chemistry, Kaohsiung Medical University, Kaohsiung City, Taiwan.
authors.forename: Chih-Hua
authors.initials: CH
authors.lastname: Tseng
authors.forename: Cherng-Chyi
authors.initials: CC
authors.lastname: Tzeng
authors.forename: Pin-Keng
authors.initials: PK
authors.lastname: Shih
authors.forename: Chia-Ning
authors.initials: CN
authors.lastname: Yang
authors.forename: You-Chung
authors.initials: YC
authors.lastname: Chuang
authors.forename: Shin-I
authors.initials: SI
authors.lastname: Peng
authors.forename: Chang-Sheng
authors.initials: CS
authors.lastname: Lin
authors.forename: Jih-Pyang
authors.initials: JP
authors.lastname: Wang
authors.forename: Chih-Mei
authors.initials: CM
authors.lastname: Cheng
authors.forename: Yeh-Long
authors.initials: YL
authors.lastname: Chen
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000138:chemical synthesis / Q000494:pharmacology* / Q000633:toxicity; D015550:Cell Degranulation / Q000187:drug effects; D002460:Cell Line; D015232:Dinoprostone / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology* / Q000633:toxicity; D007093:Imidazoles / Q000138:chemical synthesis / Q000494:pharmacology* / Q000633:toxicity; D019746:Intramolecular Oxidoreductases / Q000037:antagonists & inhibitors*; D008070:Lipopolysaccharides / Q000494:pharmacology; D008168:Lung / Q000187:drug effects / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D009504:Neutrophils / Q000187:drug effects / Q000502:physiology; D009569:Nitric Oxide / Q000378:metabolism; D000071876:Prostaglandin-E Synthases; D021281:Quantitative Structure-Activity Relationship; D051381:Rats; D017207:Rats, Sprague-Dawley; D018805:Sepsis / Q000378:metabolism / Q000473:pathology; D013481:Superoxides / Q000378:metabolism
chemical_list: D000893:Anti-Inflammatory Agents; D004791:Enzyme Inhibitors; D007093:Imidazoles; D008070:Lipopolysaccharides; D013481:Superoxides; D009569:Nitric Oxide; D019746:Intramolecular Oxidoreductases; D000071876:Prostaglandin-E Synthases; C000605865:Ptges protein, mouse; D015232:Dinoprostone