AVN-322 is a Safe Orally Bio-Available Potent and Highly Selective Antagonist of 5-HT6R with Demonstrated Ability to Improve Impaired Memory in Animal Models

Curr Alzheimer Res. 2017;14(3):268-294. doi: 10.2174/1567205013666161108105005.

Abstract

Background: In recent years, 5-hydroxytryptamine subtype 6 receptor (5-HT6 receptor, 5- HT6R) has emerged as a promising therapeutic target for the treatment of neuropathological disorders, including Alzheimer's disease (AD) and schizophrenia. 5-HT6 receptors were hypothesized to be implicated in the processes of learning, memory, and cognition with 5-HT6R antagonists being effective in animal models of cognition and memory impairment. Several selective 5-HT6R ligands are currently undergoing clinical trials for treatment of AD.

Methods: We describe results of preclinical development of a novel and highly selective and potent 5- HT6R antagonist, AVN-322, as a clinical candidate for the treatment of AD to improve concurrent debilitation of memory and cognition in the AD patients, and schizophrenia as a substance with antipsychotic effect. In the manuscript, we present its in vitro and vivo efficacy, ADME, pharmacokinetics in animals and in humans, and toxicity.

Results: While having high binding affinity in medium picomolar range, the lead compound demonstrates substantially better selectivity index then the reference drug candidates currently being tested in clinical studies. AVN-322 showed high oral bioavailability and favorable blood-brain barrier (BBB) penetration. In vivo testing revealed its clear cognition enhancing effect. AVN-322 significantly restored both scopolamine- and MK-801-induced cognitive dysfunction and demonstrated antipsychotic potential.

Conclusion: Taking into account its good safety profile and favorable pharmacokinetics, AVN-322 can be reasonably considered as a novel drug candidate for the treatment of neurological disorders such as AD and/or schizophrenia.

Keywords: 5-HT6 antagonist; Alzheimer's; CNS diseases; cognition; memory..

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Administration, Intravenous
  • Administration, Oral
  • Alzheimer Disease / drug therapy
  • Animals
  • Antipsychotic Agents / pharmacokinetics
  • Antipsychotic Agents / pharmacology
  • Antipsychotic Agents / toxicity
  • Cell Line, Tumor
  • Disease Models, Animal
  • Dogs
  • Drug Evaluation, Preclinical
  • Female
  • HEK293 Cells
  • Heterocyclic Compounds, 3-Ring / pharmacokinetics
  • Heterocyclic Compounds, 3-Ring / pharmacology*
  • Heterocyclic Compounds, 3-Ring / toxicity
  • Humans
  • Macaca mulatta
  • Male
  • Memory Disorders / drug therapy*
  • Mice
  • Nootropic Agents / pharmacokinetics
  • Nootropic Agents / pharmacology*
  • Nootropic Agents / toxicity
  • Peritoneal Absorption
  • Rats, Sprague-Dawley
  • Rats, Wistar
  • Receptors, Serotonin / metabolism
  • Schizophrenia / drug therapy
  • Serotonin Antagonists / pharmacokinetics
  • Serotonin Antagonists / pharmacology*
  • Serotonin Antagonists / toxicity

Substances

  • Antipsychotic Agents
  • Heterocyclic Compounds, 3-Ring
  • N,7-dimethyl-3-(phenylsulfonyl)-6,7,8,9-tetrahydropyrazolo(1,5-a)pyrido(3,4-e)pyrimidin-2-amine
  • Nootropic Agents
  • Receptors, Serotonin
  • Serotonin Antagonists
  • serotonin 6 receptor