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.
Download full-text PDF |
Source |
|---|---|
| http://dx.doi.org/10.2174/1567205013666161108105005 | DOI Listing |
Publication Analysis
Top Keywords
Similar Publications
Crop rotation effects on the population density of soybean soilborne pathogens under no-till cropping system.
Plant Dis
January 2025
USDA-ARS North Central Agricultural Research Laboratory, Brookings, South Dakota, United States;
Soilborne diseases are persistent problems in soybean production. Long-term crop rotation can contribute to soilborne disease management. However, the response of soilborne pathogens to crop rotation is inconsistent, and rotation efficacy is highly variable.
View Article and Find Full Text PDFBioconjugation of Synthetic Peptides onto Universal Chimeric Antigen Receptor T Cells for Targeted Cancer Immunotherapies.
ACS Nano
January 2025
Department of Bioengineering, University of Washington, Seattle, Washington 98195-5061, United States.
The recent development of modular universal chimeric antigen receptor (CAR) T-cell platforms that use bifunctional adaptor intermediates to redirect engineered T-cell effector function has greatly expanded the capabilities of adoptive T-cell therapy, enabling safer and more comprehensive cancer treatment. However, universal CAR receptor systems rely on unstable transient recognition of tag-coupled intermediates for T-cell activation, and the array of targeting intermediates has been limited to antibodies and small molecules. Addressing these shortcomings, we engineered universal CAR T-cell receptors that can be covalently modified with synthetic biomaterials by accelerated SpyCatcher003-SpyTag003 chemistry for cancer-cell targeting.
View Article and Find Full Text PDFElective Discontinuation of Larotrectinib in Pediatric Patients With TRK Fusion Sarcomas and Related Mesenchymal Tumors.
J Clin Oncol
January 2025
Children's Hospital of Philadelphia/University of Pennsylvania, Philadelphia, PA.
Larotrectinib is a highly selective tropomyosin receptor kinase (TRK) inhibitor with efficacy in children with TRK fusion tumors. We evaluated patient outcomes after elective discontinuation of larotrectinib in the absence of disease progression in a protocol-defined wait-and-see subset analysis of eligible patients where treatment resumption with larotrectinib was allowed if disease progressed. We also assessed the safety and efficacy of larotrectinib in all pediatric patients with sarcoma.
View Article and Find Full Text PDFHighly Optimized CNS Penetrant Inhibitors of EGFR Exon20 Insertion Mutations.
J Med Chem
January 2025
Pharmaron Beijing Co., Ltd., 6 Taihe Road, BDA, Beijing 100176, P. R. China.
Despite recent advances in the inhibition of EGFR (epidermal growth factor receptor), there remains a clinical need for new EGFR Exon20 insertion (Ex20Ins) inhibitors that spare EGFR WT. Herein, we report the discovery and optimization of two chemical series leading to ether and biaryl as potent, selective, and brain-penetrant inhibitors of Ex20Ins mutants. Building on our earlier discovery of alkyne which allowed access to CNS property space for an Ex20Ins inhibitor, we utilized structure-based design to move to lower lipophilicity and lower CL compounds while maintaining a WT selectivity margin.
View Article and Find Full Text PDFAlternative approaches for monitoring and evaluation of lymphatic filariasis following mass drug treatment with ivermectin, diethylcarbamazine and albendazole in East New Britain Province, Papua New Guinea.
PLoS Negl Trop Dis
January 2025
Department of Pathology, Center for Global Health and Disease, Case Western Reserve University, Cleveland, Ohio, United States of America.
Background: WHO recommends two annual rounds of mass drug administration (MDA) with ivermectin, diethylcarbamazine, and albendazole (IDA) for lymphatic filariasis (LF) elimination in treatment naïve areas that are not co-endemic for onchocerciasis such as Papua New Guinea (PNG). Whether two rounds of MDA are necessary or sufficient and the optimal sampling strategies and endpoints for stopping MDA remain undefined.
Methods And Findings: Two cross-sectional studies were conducted at baseline (N = 49 clusters or villages) and 12 months after mass drug administration (MDA) with IDA (N = 47 villages) to assess lymphatic filariasis (LF) by circulating filarial antigenemia (CFA) and microfilariae (Mf).
Want AI Summaries of new PubMed Abstracts delivered to your In-box?
Enter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!