Protein misfolding and aggregation comprise the underlying common pathological mechanism of many neurodegenerative disorders. In the case of tauopathies, a group of neurodegenerative diseases which include Alzheimer's disease and frontotemporal dementias, the hyperphosphorylation and aggregation of the microtubule (MT)-associated protein tau is believed to have pathological consequences via toxic gain and/or loss of functions. Recent studies from our laboratories have demonstrated that treatment with low weekly doses of the brain-penetrant MT-stabilizing agent, epothilone D (epoD), resulted in improved axonal transport, reduced axonal dystrophy and decreased neuronal pathology in tau transgenic (Tg) mice. These results thus suggest that compensation for the loss of tau MT-stabilizing function may be a viable therapeutic strategy for the treatment of tauopathies. However, epoD and related congeners have potentially significant deficiencies as drug candidates. Furthermore, epoD is the only example of a brain-penetrant MT-stabilizing agent that has undergone in vivo efficacy studies in tau Tg animal models. As a result, the development and evaluation of additional CNS-active MT-stabilizing agents is clearly desirable so as to identify alternative and improved clinical candidates. The focus of the proposed research plan is to investigate a related series of triazolopyrimidine, phenylpyrimidine, pyridopyridazine, pyridotriazine, and pyridazine MT-stabilizing compounds. After synthesis, compounds will be evaluated for MT-stabilizing activities, ADME-PK properties, and potential safety liabilities (Aim 1). The most promising MT-stabilizers (d15) found to be brain-penetrant and orally bioavailable will progress to an assessment of pharmacodynamic effect and acute toxicity (Aim 2), followed by longer-term 1-month safety assessments (Aim 3) to identify preferred candidates (1-2) that will undergo efficacy studies in an established Tg mouse model of tauopathy (Aim 4).

Public Health Relevance

Several lines of investigation suggest that brain-penetrant microtubule (MT)-stabilizing agents hold considerable promise as potential treatment for Alzheimer's disease and related tauopathies. However, to date, only a single brain-penetrant MT-stabilizing agent, epothilone D (epoD), has been tested in a transgenic mouse model of tauopathy. Furthermore, epoD and related congeners have potentially significant deficiencies as drug candidates, including an intravenous route of administration, P-glycoprotein interactions, and relatively complex and expensive syntheses. Thus, the focus of the proposed research plan is to investigate a related series of triazolopyrimidine, phenylpyrimidine, pyridopyridazine, pyridotriazine, and pyridazine MT- stabilizing agents to identify alternative and improved clinical candidate(s). Given their MT-stabilizing activity, favorable physical-chemical properties and synthetic accessibility, these compounds hold considerable promise as lead structures for the development of CNS-directed MT-stabilizing therapies.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
5R01AG044332-02
Application #
8670685
Study Section
Special Emphasis Panel (DDNS)
Program Officer
Refolo, Lorenzo
Project Start
2013-06-15
Project End
2018-05-31
Budget Start
2014-06-01
Budget End
2015-05-31
Support Year
2
Fiscal Year
2014
Total Cost
$478,571
Indirect Cost
$179,464
Name
University of Pennsylvania
Department
Pathology
Type
Schools of Medicine
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
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Khanna, Mansi R; Kovalevich, Jane; Lee, Virginia M-Y et al. (2016) Therapeutic strategies for the treatment of tauopathies: Hopes and challenges. Alzheimers Dement 12:1051-1065
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Cornec, Anne-Sophie; James, Michael J; Kovalevich, Jane et al. (2015) Pharmacokinetic, pharmacodynamic and metabolic characterization of a brain retentive microtubule (MT)-stabilizing triazolopyrimidine. Bioorg Med Chem Lett 25:4980-2
Lou, Kevin; Yao, Yuemang; Hoye, Adam T et al. (2014) Brain-penetrant, orally bioavailable microtubule-stabilizing small molecules are potential candidate therapeutics for Alzheimer's disease and related tauopathies. J Med Chem 57:6116-27
Brunden, Kurt R; Trojanowski, John Q; Smith 3rd, Amos B et al. (2014) Microtubule-stabilizing agents as potential therapeutics for neurodegenerative disease. Bioorg Med Chem 22:5040-9