Optimization of the choline transporter (CHT) inhibitor ML352: Development of VU6001221, an improved in vivo tool compound
| Autor: | Anna L. Blobaum, Jane Wright, Jerri M. Rook, Christopher J. Tarr, Jeanette L. Bertron, Jonathan W. Dickerson, Elizabeth A. Ennis, Charles W. Locuson, Craig W. Lindsley, Randy D. Blakely |
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| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Stereochemistry Clinical Biochemistry Pharmaceutical Science Pharmacology Biochemistry 03 medical and health sciences chemistry.chemical_compound Inhibitory Concentration 50 Structure-Activity Relationship 0302 clinical medicine Piperidines In vivo Drug Discovery Extracellular Structure–activity relationship Choline Animals Molecular Biology Oxazoles Acetylcholine receptor biology Dose-Response Relationship Drug Chemistry Membrane transport protein Organic Chemistry Membrane Transport Proteins Isoxazoles Rats Choline transporter 030104 developmental biology Nicotinic agonist Benzamides biology.protein Molecular Medicine 030217 neurology & neurosurgery Half-Life |
| Zdroj: | Bioorganicmedicinal chemistry letters. 26(19) |
| ISSN: | 1464-3405 |
| Popis: | This Letter describes the further lead optimization of the CHT inhibitor probe, ML352 (VU0476201), and the development of VU6001221, an improved in vivo tool. A multi-dimensional optimization effort encountered steep SAR, and ultimately, subtle tuning of the electronics of the central phenyl core provided VU6001221, a CHT inhibitor with comparable potency for choline uptake inhibition as ML352, yet improved PK and CNS penetration. Moreover, VU6001221 enabled evaluation, for the first time, of a CHT inhibitor in a standard preclinical rodent cognition model, novel object recognition (NOR). We observed VU6001221 to elicit a dose-responsive increase in NOR, raising the possibility of agonism of synaptic α7 nicotinic ACh receptors by elevated extracellular choline, that if confirmed would represent a novel molecular strategy to enhance cognition. |
| Databáze: | OpenAIRE |
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