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)

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.