Discovery of N-(6-(5-fluoro-2-(piperidin-1-yl)phenyl)pyridazin-3-yl)-1-(tetrahydro-2H-pyran-4-yl)methanesulfonamide as a brain-permeable and metabolically stable kynurenine monooxygenase inhibitor

Bioorg Med Chem Lett. 2021 Jul 15:44:128115. doi: 10.1016/j.bmcl.2021.128115. Epub 2021 May 17.

Abstract

Kynurenine monooxygenase (KMO) is expected to be a good drug target to treat Huntington's disease (HD). This study presents the structure-activity relationship of pyridazine derivatives to find novel KMO inhibitors. The most promising compound 14 resolved the problematic issues of lead compound 1, i.e., metabolic instability and reactive metabolite-derived side-effects. Compound 14 exhibited high brain permeability and a long-lasting pharmacokinetics profile in monkeys, and neuroprotective kynurenic acid was increased by a single administration of 14 in R6/2 mouse brain. These results demonstrated 14 may be a potential drug candidate to treat HD.

Keywords: 3-HK; BBB; Brain permeable; Huntington's disease; KMO; KYNA; Kynurenine monooxygenase; Kynurenine pathway; R6/2.

MeSH terms

  • Animals
  • Blood-Brain Barrier / drug effects*
  • Dose-Response Relationship, Drug
  • Drug Discovery*
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / metabolism
  • Enzyme Inhibitors / pharmacology*
  • Humans
  • Kynurenine 3-Monooxygenase / antagonists & inhibitors*
  • Kynurenine 3-Monooxygenase / metabolism
  • Mice
  • Molecular Structure
  • Rats
  • Structure-Activity Relationship

Substances

  • Enzyme Inhibitors
  • Kynurenine 3-Monooxygenase