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Identification of furo[3′, 2′:3,4]naphtho[1,2-d]imidazole derivatives as orally active and selective inhibitors of microsomal prostaglandin E2 synthase-1 (mPGES-1)

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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 PGE2 production, with an IC50 value of 47 nM. Compound 12 is then further examined for its inhibitory effects in the protein expression of COX-2 and microsomal prostaglandin E2 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 PGE2 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.

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Authors and Affiliations

  1. Department of Medicinal and Applied Chemistry, Kaohsiung Medical University, Kaohsiung City, 807, Taiwan

    Chih-Hua Tseng, Cherng-Chyi Tzeng, Shin-I Peng & Yeh-Long Chen

  2. Department of Biomedical Science and Environmental Biology, College of Life Science, Kaohsiung Medical University, Kaohsiung City, 807, Taiwan

    Pin-Keng Shih, Chang-Sheng Lin & Chih-Mei Cheng

  3. Institute of Biotechnology, National University of Kaohsiung, 700, Kaohsiung University Rd., Kaohsiung City, 811, Taiwan

    Chia-Ning Yang & You-Chung Chuang

  4. Department of Education and Research, Taichung Veterans General Hospital, Taichung, 407, Taiwan

    Jih-Pyang Wang

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  1. Chih-Hua Tseng
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Correspondence to Chih-Mei Cheng or Yeh-Long Chen.

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Tseng, CH., Tzeng, CC., Shih, PK. et al. Identification of furo[3′, 2′:3,4]naphtho[1,2-d]imidazole derivatives as orally active and selective inhibitors of microsomal prostaglandin E2 synthase-1 (mPGES-1). Mol Divers 16, 215–229 (2012). https://doi.org/10.1007/s11030-011-9347-9

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