Product name
UC davis is offering brain permeable anti-Amyloid beta small molecule compounds for Alzheimer therapySummary
Dual use in amyloid beta imaging and anti-Ab therapyOrganization name
UC Davis, Clinical and Translational Science CenteProfile
Alzheimer´s disease (AD) is the major cause of dementia and one of the most disabling health conditions worldwide. Previous drug development has mainly focused on compounds able to inhibit the formation of or destabilize preformed fibrillar Ab at extracellular sites.
Currently the research focus in Alzheimer's Disease has been shifted to much smaller Ab aggregates called Ab oligomers (AbO), which are potently neurotoxic in many in vitro and in vivo studies. The group of Dr. Lee-Way Jun and others previously showed that AbO can accumulate inside neurons in endosomal organelles and that the intracellular form of AbO is more toxic than extracellular soluble AbO. In fact, intraneuronal AbO may be the source of extracellular AbO, therefore represent an early lesion. None of the currently existing anti-amyloid compounds address the intraneuronal AbO.
The group intends to develop novel compounds that provide a comprehensive blockage of AbO neurotoxicity at both intraneuronal and extracellular sites. They employed a novel combinatorial chemistry and a unique high throughput cell-based screening method to discover cell-permeable and neuroprotective small molecule ligands that bind tightly and specifically to AbO. These compounds would have a dual potential use in Ab imaging and anti-Ab therapy. Most of the selected compounds have satisfactory LogP values and fulfill the Lipinski´s rule of five predictions of desirable absorption properties. In contrast to other AD drugs, the compounds can ameliorate the toxicity induced by intraneuronal Ab, a probable cause of the earliest neurotoxicity.
Completed Milestones
- Established cell-based screening methods and biophysical methods to efficiently screen and characterize a large number of compounds with rare false positive results.
- Select lead LRL compounds and (a) verify their binding to AbOand Ab fibrils in vitro and in vivo, (b) demonstrate their protective effect in reducing intraneuronal AbO levels, blocking the harmful AbO-synapse interaction and reducing cerebral levels of Ab aggregates, (c) demonstrate their oral bioavailability and brain penetration.
- Establish the EPR methods and their feasibility to analyze compound-AbO interaction. Perform initial modeling of compound-AbO interaction using molecular dynamics simulations.
Anticipated Milestones
- To demonstrate the beneficial therapeutic effect (reduction of levels of AbO and amyloid plaques, decrease in microglia activation, improvement in cognitive performance, diminished synaptic loss, etc.) by treating AD model mice with the lead compounds by oral route.
- To demonstrate reliable imaging of Ab deposits in the brain by micro-PET/CT or micro-SPECT/CT on AD model mice after intravenous injection of radiolabeled lead compounds.
- To construct a compound-Ab interaction model by a combination of electron paramagnetic resonance spectroscopy analysis and molecular dynamics simulations.
Please check the attached pdf for comprehensive structural analysis as well as in vitro and in vivo data or use the feedback link provided below for a direct contact.
Description File
Compounds_Alzheimer_0608.pdf
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