title: Pharmacokinetic, pharmacodynamic and metabolic characterization of a brain retentive microtubule (MT)-stabilizing triazolopyrimidine.
abstract: Previous studies revealed that examples of the non-naturally occurring microtubule (MT)-stabilizing triazolopyrimidines are both brain penetrant and orally bioavailable, indicating that this class of compounds may be potentially attractive in the development of MT-stabilizing therapies for the central nervous system (CNS). We now report on the pharmacokinetics (PK), pharmacodynamics (PD), and metabolism of a selected triazolopyrimidine congener, (S)-3-(4-(5-chloro-7-((1,1,1-trifluoropropan-2-yl)amino)-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)-3,5-difluorophenoxy)-propan-1-ol (4). These studies revealed that 4 exhibits longer brain than plasma half-life that may be exploited to achieve a selective accumulation of the compound within the CNS. Furthermore, compound metabolism studies suggest that in plasma 4 is rapidly oxidized at the terminal hydroxyl group to form a comparatively inactive carboxylic acid metabolite. Peripheral administration of relatively low doses of 4 to normal mice was found to produce a significant elevation in acetylated α-tubulin, a marker of stable MTs, in the brain. Collectively, these results indicate that 4 may effectively target brain MTs at doses that produce minimal peripheral exposure.
authors.affiliation: Department of Chemistry, School of Arts and Sciences, University of Pennsylvania, 231 South 34th St., Philadelphia, PA 19104-6323, United States.
authors.forename: Anne-Sophie
authors.initials: AS
authors.lastname: Cornec
authors.affiliation: Center for Neurodegenerative Disease Research, Institute on Aging, University of Pennsylvania, 3600 Spruce Street, Philadelphia, PA 19104-6323, United States.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: James
authors.affiliation: Center for Neurodegenerative Disease Research, Institute on Aging, University of Pennsylvania, 3600 Spruce Street, Philadelphia, PA 19104-6323, United States.
authors.forename: Jane
authors.initials: J
authors.lastname: Kovalevich
authors.affiliation: Center for Neurodegenerative Disease Research, Institute on Aging, University of Pennsylvania, 3600 Spruce Street, Philadelphia, PA 19104-6323, United States.
authors.forename: John Q
authors.initials: JQ
authors.lastname: Trojanowski
authors.affiliation: Center for Neurodegenerative Disease Research, Institute on Aging, University of Pennsylvania, 3600 Spruce Street, Philadelphia, PA 19104-6323, United States.
authors.forename: Virginia M-Y
authors.initials: VM
authors.lastname: Lee
authors.affiliation: Department of Chemistry, School of Arts and Sciences, University of Pennsylvania, 231 South 34th St., Philadelphia, PA 19104-6323, United States. Electronic address: smithab@sas.upenn.edu.
authors.forename: Amos B
authors.initials: AB
authors.lastname: Smith
authors.affiliation: Department of Chemistry, School of Arts and Sciences, University of Pennsylvania, 231 South 34th St., Philadelphia, PA 19104-6323, United States; Center for Neurodegenerative Disease Research, Institute on Aging, University of Pennsylvania, 3600 Spruce Street, Philadelphia, PA 19104-6323, United States. Electronic address: 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, 3600 Spruce Street, Philadelphia, PA 19104-6323, United States. Electronic address: kbrunden@upenn.edu.
authors.forename: Kurt R
authors.initials: KR
authors.lastname: Brunden
mesh_terms: D000818:Animals; D001921:Brain / Q000378:metabolism*; D051379:Mice; D008870:Microtubules / Q000378:metabolism*; D008968:Molecular Conformation; D011743:Pyrimidines / Q000008:administration & dosage / Q000378:metabolism* / Q000493:pharmacokinetics*; D014230:Triazoles / Q000008:administration & dosage / Q000378:metabolism* / Q000493:pharmacokinetics*
chemical_list: C000608373:3-(4-(5-chloro-7-((1,1,1-trifluoropropan-2-yl)amino)-(1,2,4)triazolo(1,5-a)pyrimidin-6-yl)-3,5-difluorophenoxy)-propan-1-ol; D011743:Pyrimidines; D014230:Triazoles
keywords: CNS drug discovery; Microtubule stabilization; Pharmacodynamic; Pharmacokinetic; Triazolopyrimidine
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