title: AVN-211, Novel and Highly Selective 5-HT6 Receptor Small Molecule Antagonist, for the Treatment of Alzheimer's Disease.
abstract: Within the past decade several novel targets have been indicated as key players in Alzheimer-type dementia and associated conditions, including a "frightening" memory loss as well as severe cognitive impairments. These proteins are deeply implicated in crucial cell processes, e.g., autophagy, growth and progression, apoptosis, and metabolic equilibrium. Since recently, 5-HT6R has been considered as one of the most prominent biological targets in AD drug therapy. Therefore, we investigated the potential procognitive and neuroprotective effects of our novel selective 5-HT6R antagonist, AVN-211. During an extensive preclinical evaluation the lead compound demonstrated a relatively high therapeutic potential and improved selectivity toward 5-HT6R as compared to reference drug candidates. It was thoroughly examined in different in vivo behavioral models directly related to AD and showed evident improvements in cognition and learning. In many cases, the observed effect was considerably greater than that determined for the reported drugs and drug candidates, including memantine, SB-742457, and Lu AE58054, evaluated under the same conditions. In addition, AVN-211 showed a similar or better anxiolytic efficacy than fenobam, rufinamide, lorazepam, and buspirone in an elevated plus-maze model, elevated platform, and open field tests. The compound demonstrated low toxicity and no side effects in vivo, an appropriate pharmacokinetic profile, and stability. In conclusion, AVN-211 significantly delayed or partially halted the progressive decline in memory function associated with AD, which makes it an interesting drug candidate for the treatment of neurodegenerative and psychiatric disorders. Advanced clinical trials are currently under active discussion and in high priority.
authors.affiliation: Alla Chem LLC , 1835 East Hallandale Beach Boulevard, #442, Hallandale Beach, Florida 33009, United States.|Avineuro Pharmaceuticals, Inc. , 1835 East Hallandale Beach Boulevard, #442, Hallandale Beach, Florida 33009, United States.
authors.forename: Alexandre V
authors.initials: AV
authors.lastname: Ivachtchenko
authors.affiliation: R-Pharm Overseas, Inc. , 12526 High Bluff Drive, Suite #300, San Diego, California 92130, United States.
authors.forename: Yan
authors.initials: Y
authors.lastname: Lavrovsky
authors.affiliation: Moscow Institute of Physics and Technology (State University) , 9 Institutskiy Lane, Dolgoprudny City, Moscow Region 141700, Russian Federation.|Chemistry Department, Moscow State University , Leninskie Gory, Building 1/3, GSP-1, 119991, Moscow, Russia.
authors.forename: Yan A
authors.initials: YA
authors.lastname: Ivanenkov
mesh_terms: D000544:Alzheimer Disease / Q000188:drug therapy*; D000818:Animals; D018938:Caco-2 Cells; D002463:Cell Membrane Permeability / Q000187:drug effects; D057166:High-Throughput Screening Assays; D006801:Humans; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D008253:Macaca mulatta; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D018696:Neuroprotective Agents / Q000493:pharmacokinetics / Q000494:pharmacology*; D011720:Pyrazoles / Q000493:pharmacokinetics / Q000494:pharmacology*; D011743:Pyrimidines / Q000493:pharmacokinetics / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar; D011985:Receptors, Serotonin / Q000737:chemistry* / Q000378:metabolism; D014018:Tissue Distribution
chemical_list: C000609554:3-sulfonyl-pyrazolo(1,5-a)pyrimidine; D018696:Neuroprotective Agents; D011720:Pyrazoles; D011743:Pyrimidines; D011985:Receptors, Serotonin; C097216:serotonin 6 receptor
keywords: 5-HT6R; Alzheimer’s disease; antagonists; pharmacokinetics; preclinical study; selectivity