In:
Current Alzheimer Research, Bentham Science Publishers Ltd., Vol. 14, No. 3 ( 2017-03), p. 268-294
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.
Type of Medium:
Online Resource
ISSN:
1567-2050
DOI:
10.2174/1567205013666161108105005
Language:
English
Publisher:
Bentham Science Publishers Ltd.
Publication Date:
2017