Multitargeted Imidazoles: Potential Therapeutic Leads for Alzheimer’s and Other Neurodegenerative Diseases

• Published in: Journal of medicinal chemistry 2017-06, Vol.60 (12), p.5120-5145
• Main Authors: Cornec, Anne-Sophie, Monti, Ludovica, Kovalevich, Jane, Makani, Vishruti, James, Michael J, Vijayendran, Krishna G, Oukoloff, Killian, Yao, Yuemang, Lee, Virginia M.-Y, Trojanowski, John Q, Smith, Amos B, Brunden, Kurt R, Ballatore, Carlo
• Format: Article
• Language: English
• Subjects: Alzheimer Disease - drug therapy; Animals; Arachidonate 5-Lipoxygenase - metabolism; Chemistry Techniques, Synthetic; Cyclooxygenase Inhibitors - chemistry; Cyclooxygenase Inhibitors - pharmacology; Drug Evaluation, Preclinical - methods; Female; Humans; Imidazoles - chemistry; Imidazoles - pharmacology; Leukotrienes - biosynthesis; Lipoxygenase Inhibitors - chemistry; Lipoxygenase Inhibitors - pharmacology; Male; Mice, Inbred Strains; Microtubules - drug effects; Microtubules - metabolism; Molecular Targeted Therapy; Neurodegenerative Diseases - drug therapy; Prostaglandins - metabolism; Rats; Structure-Activity Relationship
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/acs.jmedchem.7b00475

Alzheimer’s disease (AD) is a complex, multifactorial disease in which different neuropathological mechanisms are likely involved, including those associated with pathological tau and Aβ species as well as neuroinflammation. In this context, the development of single multitargeted therapeutics directed against two or more disease mechanisms could be advantageous. Starting from a series of 1,5-diarylimidazoles with microtubule (MT)-stabilizing activity and structural similarities with known NSAIDs, we conducted structure–activity relationship studies that led to the identification of multitargeted prototypes with activities as MT-stabilizing agents and/or inhibitors of the cyclooxygenase (COX) and 5-lipoxygenase (5-LOX) pathways. Several examples are brain-penetrant and exhibit balanced multitargeted in vitro activity in the low μM range. As brain-penetrant MT-stabilizing agents have proven effective against tau-mediated neurodegeneration in animal models, and because COX- and 5-LOX-derived eicosanoids are thought to contribute to Aβ plaque deposition, these 1,5-diarylimidazoles provide tools to explore novel multitargeted strategies for AD and other neurodegenerative diseases.