A novel neuroregenerative approach using ET(B) receptor agonist, IRL-1620, to treat CNS disorders

Physiol Res. 2018 Jun 27;67(Suppl 1):S95-S113. doi: 10.33549/physiolres.933859.

Abstract

Endothelin B (ET(B)) receptors present in abundance the central nervous system (CNS) have been shown to have significant implications in its development and neurogenesis. We have targeted ET(B) receptors stimulation using a highly specific agonist, IRL-1620, to treat CNS disorders. In a rat model of cerebral ischemia intravenous administration IRL-1620 significantly reduced infarct volume and improved neurological and motor functions compared to control. This improvement, in part, is due to an increase in neuroregeneration. We also investigated the role of IRL-1620 in animal models of Alzheimer's disease (AD). IRL-1620 improved learning and memory, reduced oxidative stress and increased VEGF and NGF in Abeta treated rats. IRL-1620 also improved learning and memory in an aged APP/PS1 transgenic mouse model of AD. These promising findings prompted us to initiate human studies. Successful chemistry, manufacturing and control along with mice, rat and dog toxicological studies led to completion of a human Phase I study in healthy volunteers. We found that a dose of 0.6 microg/kg of IRL-1620 can be safely administered, three times every four hours, without any adverse effect. A Phase II clinical study with IRL-1620 has been initiated in patients with cerebral ischemia and mild to moderate AD.

Publication types

  • Review

MeSH terms

  • Animals
  • Central Nervous System Diseases / drug therapy
  • Central Nervous System Diseases / metabolism
  • Clinical Trials as Topic / methods
  • Drug Evaluation, Preclinical / methods
  • Endothelins / pharmacology
  • Endothelins / therapeutic use*
  • Humans
  • Nerve Regeneration / drug effects*
  • Nerve Regeneration / physiology
  • Neurodegenerative Diseases / drug therapy*
  • Neurodegenerative Diseases / metabolism
  • Oxidative Stress / drug effects
  • Oxidative Stress / physiology
  • Peptide Fragments / pharmacology
  • Peptide Fragments / therapeutic use*
  • Receptor, Endothelin B / agonists*
  • Receptor, Endothelin B / metabolism

Substances

  • Endothelins
  • Peptide Fragments
  • Receptor, Endothelin B
  • IRL 1620