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Microtubule-Stabilizing 1,2,4-Triazolo[1,5-a]pyrimidines as Candidate Therapeutics for Neurodegenerative Disease: Matched Molecular Pair Analyses and Computational Studies Reveal New Structure-Activity Insights
- Source :
- Journal of medicinal chemistry, vol 66, iss 1
- Publication Year :
- 2023
- Publisher :
- eScholarship, University of California, 2023.
-
Abstract
- Microtubule (MT)-stabilizing 1,2,4-triazolo[1,5-a]pyrimidines (TPDs) hold promise as candidate therapeutics for Alzheimer's disease (AD) and other neurodegenerative conditions. However, depending on the choice of substituents around the TPD core, these compounds can elicit markedly different cellular phenotypes that likely arise from the interaction of TPD congeners with either one or two spatially distinct binding sites within tubulin heterodimers (i.e., the seventh site and the vinca site). In the present study, we report the design, synthesis, and evaluation of a series of new TPD congeners, as well as matched molecular pair analyses and computational studies, that further elucidate the structure-activity relationships of MT-active TPDs. These studies led to the identification of novel MT-normalizing TPD candidates that exhibit favorable ADME-PK, including brain penetration and oral bioavailability, as well as brain pharmacodynamic activity.
- Subjects :
- Aging
Medicinal & Biomolecular Chemistry
Organic Chemistry
Neurosciences
Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD)
Neurodegenerative Diseases
Pharmacology and Pharmaceutical Sciences
Neurodegenerative
Alzheimer's Disease
Microtubules
Brain Disorders
Structure-Activity Relationship
Medicinal and Biomolecular Chemistry
Pyrimidines
Alzheimer Disease
Tubulin
Drug Discovery
Neurological
Acquired Cognitive Impairment
Molecular Medicine
Humans
Dementia
Subjects
Details
- Database :
- OpenAIRE
- Journal :
- Journal of medicinal chemistry, vol 66, iss 1
- Accession number :
- edsair.doi.dedup.....eec72b970204417d9dd0cef026d13404