This letter describes the synthesis and biological evaluation of furan and dihydrofuran-fused tricyclic benzo[d]imidazole derivatives as novel mPGES-1 inhibitors, capable of inhibiting an increased PGE₂ production in the disease state. Structure-activity optimization afforded many potent mPGES-1 inhibitors having <50 nM potencies in the A549 cellular assay and adequate metabolic stability in liver microsomes. Lead compounds 8l and 8m demonstrated reasonable in vitro pharmacology and pharmacokinetic properties over other compounds. In particular, 8m revealed satisfactory oral pharmacokinetics and bioavailability in multiple species like rat, guinea pig, dog and cynomolgus monkey. In addition, the representative compound 8m showed in vivo efficacy by inhibiting LPS-induced thermal hyperalgesia with an ED₅₀ of 14.3 mg/kg in guinea pig.

这封信描述了呋喃和二氢呋喃稠合的三环苯并[ d ]咪唑衍生物作为新型mPGES-1抑制剂的合成和生物学评估，它们能够在疾病状态下抑制PGE ₂产生的增加。结构活性的优化提供了许多有效的mPGES-1抑制剂，在A549细胞分析中的效价<50 nM，并且在肝微粒体中具有足够的代谢稳定性。与其他化合物相比，先导化合物8l和8m具有合理的体外药理学和药代动力学特性。特别是8m揭示了在大鼠，豚鼠，狗和食蟹猴等多种物种中令人满意的口服药代动力学和生物利用度。另外，代表性化合物8m在豚鼠中通过以14.3mg / kg的ED ₅₀抑制LPS诱导的热痛觉过敏显示出体内功效。