Amyloid-β1-42 (Aβ42) peptide aggregate formation in the brain plays a crucial role in the onset and progression of Alzheimer's disease. According to published research, the Aβ monomer's amino acid residues KLVFF (16-20) self-associate to create antiparallel β-sheet fibrils. Small compounds can prevent self-assembly and destroy Aβ fibrils by attaching to the Aβ16-20 regions of Aβ42. To enhance biological characteristics and binding affinity to the amyloid beta peptide, β-sheet breaker small molecules can be developed and modified with various scaffolds. In the current study, a novel series of 2,3-disubstitutedbenzofuran derivatives was designed and created by fusing the benzofuran core of a known iron chelator, neuroprotective, and neurorestorative agent, like VK-28, with a motif found in the structure of a known muscarinic inhibitor and amyloid binding agent, like SKF-64346. Measurements of the binding affinity and in vitro aggregation inhibition of the Aβ42 peptide were made using the thioflavin T (ThT) test. Using AutoDock 4.2 software, molecular docking studies of the synthesized compounds were performed on the monomer and fibril structures of amyloid beta peptide. The compounds 8a-8g exhibited strong binding energy and affinity to Aβ fibrils as well as a 50%-67% reduction of the growth of Aβ aggregation. Finally, the positive traits of our recently synthesized compounds make them excellent candidates for additional in vivo testing as a "β-sheet breaking agent."

01 Oct 2021·Free Radical Biology and MedicineQ2 · MEDICINE

The protective, rescue and therapeutic potential of multi-target iron-chelators for retinitis pigmentosa

Q2 · MEDICINE

Review

Author: Youdim, Moussa B H ; Lin, Bin

Retinitis pigmentosa (RP) is a group of inherited diseases in which mutations result in the initial loss of night vision, followed by complete blindness. There is currently no effective therapeutic option for RP patients. Given the extremely heterogeneous nature of RP, any causative gene-specific therapy would be practical in a small fraction of patients with RP. Non-gene-specific therapeutics that is applicable to the majority of RP patients regardless of causative mutations may have an enormous impact on RP treatment. Several theories including apoptosis, oxidative stress and neuroinflammation have been proposed as possible underlying mechanisms for photoreceptor death in RP. We have designed and synthesized a series of iron-chelating compounds that possess diverse pharmacological properties and can act in a non-gene-specific manner on multiple pathological features ascribed to Alzheimer's disease, Parkinson's disease and RP. In this review, we discuss the multiple effects of several brain-permeable multi target iron-chelating compounds on photoreceptor degeneration in a mouse model of human RP. Specifically, we focus on the anti-apototic, neuroprotective and neurorescue effects of the compound VK28, M30 and VAR10303 on the histologic and functional preservation of photoreceptors in a mouse model of RP. We consider such drugs as potential therapeutic agents for RP patients.

26 Oct 2020·Current Pharmaceutical DesignQ4 · MEDICINE

Exploring the Multifunctional Neuroprotective Promise of Rasagiline Derivatives for Multi-Dysfunctional Alzheimer’s Disease

Q4 · MEDICINE

Article

Author: Kabir, Md Tanvir ; Alim, Md Abdul ; Khatkar, Anurag ; Ashraf, Ghulam Md ; Rauf, Abdur ; Al Mamun, Abdullah ; Uddin, Md Sahab ; Rahman, Md Habibur ; Rahman, Md Motiar ; Mathew, Bijo

Alzheimer's disease (AD) is a chronic, age-related, and irreversible brain disorder that typically develops slowly and gets worse over time. The potent auspicious drug candidate for the treatment of AD is supposed to perform the simultaneous modulation of several targets linked to AD. The new therapeutic approach involves drug candidates that are designed to act on multiple targets and have various pharmacological properties. This trend has triggered the development of various multimodal drugs including TV-3326 (i.e. ladostigil) and M-30 (i.e. a new multitarget iron chelator). TV-3326 combines the neurorestorative/neuroprotective effects of the cholinesterase (ChE) inhibitory activity of rivastigmine with rasagiline (a selective monoamine oxidase-B inhibitor and novel antiparkinsonian agent) in a single molecule. M-30, the second derivative of rasagiline, was developed by combining the propargyl moiety of rasagiline into the skeleton of VK-28 (i.e. a novel brain permeable neuroprotective iron chelator). It has been revealed that both the compounds possess anti-AD effects and therefore, the clinical development is directed to the treatment of this type of neurodegenerative diseases (NDs). In this article, we have reviewed the neuroprotective molecular mechanisms and multimodal effects of TV-3326 and M-30.

100 Deals associated with VAR-10100

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Indication	Highest Phase	Country/Location	Organization	Date
Nervous System Diseases	Discovery	IL	Varinel, Inc.	-
Wounds and Injuries	Discovery	IL	Varinel, Inc.	-

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