一种口服安全的生物可利用的强效和高选择性5-HT6R拮抗剂：AVN-322能改善动物模型的记忆受损

Title: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

Volume: 14 Issue: 3

Author(s): Alexandre V. Ivachtchenko, Yan A. Ivanenkov, Mark S. Veselov, I. M. Okun.

Affiliation:

关键词: 阿尔茨海默症，认知，中枢神经系统疾病，5-羟色胺6受体拮抗剂，记忆

摘要: 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.

Cite this article as:

Alexandre V. Ivachtchenko, Yan A. Ivanenkov, Mark S. Veselov, I. M. Okun. , 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, Current Alzheimer Research 2017; 14 (3) . https://dx.doi.org/10.2174/1567205013666161108105005

DOI https://dx.doi.org/10.2174/1567205013666161108105005	Print ISSN 1567-2050
Publisher Name Bentham Science Publisher	Online ISSN 1875-5828