Discovery of furan and dihydrofuran-fused tricyclic benzo[d]imidazole derivatives as potent and orally efficacious microsomal prostaglandin E synthase-1 (mPGES-1) inhibitors: Part-1

Bioorg Med Chem Lett. 2017 Dec 1;27(23):5131-5138. doi: 10.1016/j.bmcl.2017.10.062.

Abstract

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.

Keywords: Benzofuran; Hyperalgesia; Inflammation; Osteoarthritis; PGE(2); Prostanoid; Scaffold hopping.

MeSH terms

  • A549 Cells
  • Administration, Oral
  • Animals
  • Dogs
  • Enzyme Inhibitors / chemistry*
  • Enzyme Inhibitors / pharmacokinetics
  • Enzyme Inhibitors / therapeutic use
  • Furans / chemistry*
  • Guinea Pigs
  • Half-Life
  • Humans
  • Hyperalgesia / drug therapy
  • Imidazoles / chemistry*
  • Imidazoles / pharmacokinetics
  • Imidazoles / therapeutic use
  • Inhibitory Concentration 50
  • Macaca fascicularis
  • Microsomes, Liver / metabolism
  • Prostaglandin-E Synthases / antagonists & inhibitors*
  • Prostaglandin-E Synthases / metabolism
  • Rats
  • Solubility
  • Structure-Activity Relationship

Substances

  • Enzyme Inhibitors
  • Furans
  • Imidazoles
  • Prostaglandin-E Synthases