title: Characterization of Brain-Penetrant Pyrimidine-Containing Molecules with Differential Microtubule-Stabilizing Activities Developed as Potential Therapeutic Agents for Alzheimer's Disease and Related Tauopathies.
abstract: The microtubule (MT)-stabilizing protein tau disengages from MTs and forms intracellular inclusions known as neurofibrillary tangles in Alzheimer's disease and related tauopathies. Reduced tau binding to MTs in tauopathies may contribute to neuronal dysfunction through decreased MT stabilization and disrupted axonal transport. Thus, the introduction of brain-penetrant MT-stabilizing compounds might normalize MT dynamics and axonal deficits in these disorders. We previously described a number of phenylpyrimidines and triazolopyrimidines (TPDs) that induce tubulin post-translational modifications indicative of MT stabilization. We now further characterize the biologic properties of these small molecules, and our results reveal that these compounds can be divided into two general classes based on the cellular response they evoke. One group composed of the phenylpyrimidines and several TPD examples showed a bell-shaped concentration-response effect on markers of MT stabilization in cellular assays. Moreover, these compounds induced proteasome-dependent degradation of α- and β-tubulin and caused altered MT morphology in both dividing cells and neuron cultures. In contrast, a second group comprising a subset of TPD molecules (TPD+) increased markers of stable MTs in a concentration-dependent manner in dividing cells and in neurons without affecting total tubulin levels or disrupting MT architecture. Moreover, an example TPD+ compound was shown to increase MTs in a neuron culture model with induced tau hyperphosphorylation and associated MT deficits. Several TPD+ compounds were shown to be both brain penetrant and orally bioavailable, and a TPD+ example increased MT stabilization in the mouse brain, making these compounds potential candidate therapeutics for neurodegenerative tauopathies such as Alzheimer's disease.
authors.affiliation: Center for Neurodegenerative Disease Research, Institute on Aging, University of Pennsylvania, Philadelphia, Pennsylvania (J.K., A.-S.C., Y.Y., M.J., V.M.-Y.L., J.Q.T., C.B., K.R.B.); and Department of Chemistry, School of Arts and Sciences, University of Pennsylvania, Philadelphia, Pennsylvania (A.-S.C., A.B.S., C.B.).
authors.forename: Jane
authors.initials: J
authors.lastname: Kovalevich
authors.affiliation: Center for Neurodegenerative Disease Research, Institute on Aging, University of Pennsylvania, Philadelphia, Pennsylvania (J.K., A.-S.C., Y.Y., M.J., V.M.-Y.L., J.Q.T., C.B., K.R.B.); and Department of Chemistry, School of Arts and Sciences, University of Pennsylvania, Philadelphia, Pennsylvania (A.-S.C., A.B.S., C.B.).
authors.forename: Anne-Sophie
authors.initials: AS
authors.lastname: Cornec
authors.affiliation: Center for Neurodegenerative Disease Research, Institute on Aging, University of Pennsylvania, Philadelphia, Pennsylvania (J.K., A.-S.C., Y.Y., M.J., V.M.-Y.L., J.Q.T., C.B., K.R.B.); and Department of Chemistry, School of Arts and Sciences, University of Pennsylvania, Philadelphia, Pennsylvania (A.-S.C., A.B.S., C.B.).
authors.forename: Yuemang
authors.initials: Y
authors.lastname: Yao
authors.affiliation: Center for Neurodegenerative Disease Research, Institute on Aging, University of Pennsylvania, Philadelphia, Pennsylvania (J.K., A.-S.C., Y.Y., M.J., V.M.-Y.L., J.Q.T., C.B., K.R.B.); and Department of Chemistry, School of Arts and Sciences, University of Pennsylvania, Philadelphia, Pennsylvania (A.-S.C., A.B.S., C.B.).
authors.forename: Michael
authors.initials: M
authors.lastname: James
authors.affiliation: Center for Neurodegenerative Disease Research, Institute on Aging, University of Pennsylvania, Philadelphia, Pennsylvania (J.K., A.-S.C., Y.Y., M.J., V.M.-Y.L., J.Q.T., C.B., K.R.B.); and Department of Chemistry, School of Arts and Sciences, University of Pennsylvania, Philadelphia, Pennsylvania (A.-S.C., A.B.S., C.B.).
authors.forename: Alexander
authors.initials: A
authors.lastname: Crowe
authors.affiliation: Center for Neurodegenerative Disease Research, Institute on Aging, University of Pennsylvania, Philadelphia, Pennsylvania (J.K., A.-S.C., Y.Y., M.J., V.M.-Y.L., J.Q.T., C.B., K.R.B.); and Department of Chemistry, School of Arts and Sciences, University of Pennsylvania, Philadelphia, Pennsylvania (A.-S.C., A.B.S., C.B.).
authors.forename: Virginia M-Y
authors.initials: VM
authors.lastname: Lee
authors.affiliation: Center for Neurodegenerative Disease Research, Institute on Aging, University of Pennsylvania, Philadelphia, Pennsylvania (J.K., A.-S.C., Y.Y., M.J., V.M.-Y.L., J.Q.T., C.B., K.R.B.); and Department of Chemistry, School of Arts and Sciences, University of Pennsylvania, Philadelphia, Pennsylvania (A.-S.C., A.B.S., C.B.).
authors.forename: John Q
authors.initials: JQ
authors.lastname: Trojanowski
authors.affiliation: Center for Neurodegenerative Disease Research, Institute on Aging, University of Pennsylvania, Philadelphia, Pennsylvania (J.K., A.-S.C., Y.Y., M.J., V.M.-Y.L., J.Q.T., C.B., K.R.B.); and Department of Chemistry, School of Arts and Sciences, University of Pennsylvania, Philadelphia, Pennsylvania (A.-S.C., A.B.S., C.B.).
authors.forename: Amos B
authors.initials: AB
authors.lastname: Smith
authors.affiliation: Center for Neurodegenerative Disease Research, Institute on Aging, University of Pennsylvania, Philadelphia, Pennsylvania (J.K., A.-S.C., Y.Y., M.J., V.M.-Y.L., J.Q.T., C.B., K.R.B.); and Department of Chemistry, School of Arts and Sciences, University of Pennsylvania, Philadelphia, Pennsylvania (A.-S.C., A.B.S., C.B.) kbrunden@upenn.edu bcarlo@sas.upenn.edu.
authors.forename: Carlo
authors.initials: C
authors.lastname: Ballatore
authors.affiliation: Center for Neurodegenerative Disease Research, Institute on Aging, University of Pennsylvania, Philadelphia, Pennsylvania (J.K., A.-S.C., Y.Y., M.J., V.M.-Y.L., J.Q.T., C.B., K.R.B.); and Department of Chemistry, School of Arts and Sciences, University of Pennsylvania, Philadelphia, Pennsylvania (A.-S.C., A.B.S., C.B.) kbrunden@upenn.edu bcarlo@sas.upenn.edu.
authors.forename: Kurt R
authors.initials: KR
authors.lastname: Brunden
mesh_terms: D000544:Alzheimer Disease / Q000188:drug therapy*; D000818:Animals; D001682:Biological Availability; D001812:Blood-Brain Barrier / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D005260:Female; D006846:Hydrocarbons, Halogenated / Q000493:pharmacokinetics / Q000627:therapeutic use*; D008297:Male; D051379:Mice; D008870:Microtubules / Q000187:drug effects*; D009474:Neurons / Q000187:drug effects; D046988:Proteasome Endopeptidase Complex / Q000187:drug effects; D011743:Pyrimidines / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use*; D024801:Tauopathies / Q000188:drug therapy*; D014230:Triazoles / Q000493:pharmacokinetics / Q000627:therapeutic use*; D014404:Tubulin / Q000235:genetics / Q000378:metabolism; D016875:tau Proteins / Q000378:metabolism
chemical_list: D006846:Hydrocarbons, Halogenated; D011743:Pyrimidines; D014230:Triazoles; D014404:Tubulin; D016875:tau Proteins; D046988:Proteasome Endopeptidase Complex; C521494:cevipabulin