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.
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.



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.



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.



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.
Alexandre V
AV
Ivachtchenko
Yan A
YA
Ivanenkov
Mark S
MS
Veselov
5924 Seacrest View Rd., San Diego, CA 92121, United States.
I M
IM
Okun
D061605:Administration, Intravenous; D000284:Administration, Oral; D000544:Alzheimer Disease / Q000188:drug therapy; D000818:Animals; D014150:Antipsychotic Agents / Q000493:pharmacokinetics / Q000494:pharmacology / Q000633:toxicity; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D004285:Dogs; D004353:Drug Evaluation, Preclinical; D005260:Female; D057809:HEK293 Cells; D006575:Heterocyclic Compounds, 3-Ring / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000633:toxicity; D006801:Humans; D008253:Macaca mulatta; D008297:Male; D008569:Memory Disorders / Q000188:drug therapy*; D051379:Mice; D018697:Nootropic Agents / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000633:toxicity; D065629:Peritoneal Absorption; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar; D011985:Receptors, Serotonin / Q000378:metabolism; D012559:Schizophrenia / Q000188:drug therapy; D012702:Serotonin Antagonists / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000633:toxicity
D014150:Antipsychotic Agents; D006575:Heterocyclic Compounds, 3-Ring; C000623333:N,7-dimethyl-3-(phenylsulfonyl)-6,7,8,9-tetrahydropyrazolo(1,5-a)pyrido(3,4-e)pyrimidin-2-amine; D018697:Nootropic Agents; D011985:Receptors, Serotonin; D012702:Serotonin Antagonists; C097216:serotonin 6 receptor
5-HT6 antagonist; Alzheimer's; CNS diseases; cognition; memory.