title: Brain-penetrant, orally bioavailable microtubule-stabilizing small molecules are potential candidate therapeutics for Alzheimer's disease and related tauopathies.
abstract: Microtubule (MT) stabilizing drugs hold promise as potential treatments for Alzheimer's disease (AD) and related tauopathies. However, thus far epothilone D has been the only brain-penetrant MT-stabilizer to be evaluated in tau transgenic mice and in AD patients. Furthermore, this natural product exhibits potential deficiencies as a drug candidate, including an intravenous route of administration and the inhibition of the P-glycoprotein (Pgp) transporter. Thus, the identification of alternative CNS-active MT-stabilizing agents that lack these potential limitations is of interest. Toward this objective, we have evaluated representative compounds from known classes of non-naturally occurring MT-stabilizing small molecules. This led to the identification of selected triazolopyrimidines and phenylpyrimidines that are orally bioavailable and brain-penetrant without disruption of Pgp function. Pharmacodynamic studies confirmed that representative compounds from these series enhance MT-stabilization in the brains of wild-type mice. Thus, these classes of MT-stabilizers hold promise for the development of orally active, CNS-directed MT-stabilizing therapies.
authors.affiliation: Department of Chemistry, School of Arts and Sciences, University of Pennsylvania , 231 South 34th Street, Philadelphia, Pennsylvania 19104-6323, United States.
authors.forename: Kevin
authors.initials: K
authors.lastname: Lou
authors.forename: Yuemang
authors.initials: Y
authors.lastname: Yao
authors.forename: Adam T
authors.initials: AT
authors.lastname: Hoye
authors.forename: Michael J
authors.initials: MJ
authors.lastname: James
authors.forename: Anne-Sophie
authors.initials: AS
authors.lastname: Cornec
authors.forename: Edward
authors.initials: E
authors.lastname: Hyde
authors.forename: Bryant
authors.initials: B
authors.lastname: Gay
authors.forename: Virginia M-Y
authors.initials: VM
authors.lastname: Lee
authors.forename: John Q
authors.initials: JQ
authors.lastname: Trojanowski
authors.forename: Amos B
authors.initials: AB
authors.lastname: Smith
authors.forename: Kurt R
authors.initials: KR
authors.lastname: Brunden
authors.forename: Carlo
authors.initials: C
authors.lastname: Ballatore
mesh_terms: D000284:Administration, Oral; D000544:Alzheimer Disease / Q000188:drug therapy / Q000473:pathology; D000818:Animals; D001682:Biological Availability; D001921:Brain / Q000378:metabolism*; D002460:Cell Line; D006801:Humans; D051379:Mice; D008870:Microtubules / Q000187:drug effects* / Q000378:metabolism; D015394:Molecular Structure; D011743:Pyrimidines / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D024801:Tauopathies / Q000188:drug therapy* / Q000473:pathology
chemical_list: D011743:Pyrimidines