Advantages of brain penetrating inhibitors of kynurenine-3-monooxygenase for treatment of neurodegenerative diseases

Arch Biochem Biophys. 2021 Jan 15:697:108702. doi: 10.1016/j.abb.2020.108702. Epub 2020 Dec 1.

Abstract

Kynurenine-3-monooxygenase (KMO) is an important therapeutic target for several brain disorders that has been extensively studied in recent years. Potent inhibitors towards KMO have been developed and tested within different disease models, showing great therapeutic potential, especially in models of neurodegenerative disease. The inhibition of KMO reduces the production of downstream toxic kynurenine pathway metabolites and shifts the flux to the formation of the neuroprotectant kynurenic acid. However, the efficacy of KMO inhibitors in neurodegenerative disease has been limited by their poor brain permeability. Combined with virtual screening and prodrug strategies, a novel brain penetrating KMO inhibitor has been developed which dramatically decreases neurotoxic metabolites. This review highlights the importance of KMO as a drug target in neurological disease and the benefits of brain permeable inhibitors in modulating kynurenine pathway metabolites in the central nervous system.

Keywords: Brain penetrance; Inhibitor; Kynurenine-3-monooxygenase; Neurodegenerative disease; Prodrug.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Animals
  • Brain / drug effects
  • Brain / metabolism*
  • Drug Discovery
  • Enzyme Inhibitors / metabolism*
  • Enzyme Inhibitors / pharmacology*
  • Enzyme Inhibitors / therapeutic use
  • Humans
  • Kynurenine 3-Monooxygenase / antagonists & inhibitors*
  • Neurodegenerative Diseases / drug therapy*
  • Neurodegenerative Diseases / enzymology
  • Neurodegenerative Diseases / metabolism

Substances

  • Enzyme Inhibitors
  • Kynurenine 3-Monooxygenase