title: Discovery of brain-penetrant, orally bioavailable aminothienopyridazine inhibitors of tau aggregation.
abstract: Agents capable of preventing the misfolding and sequestration of the microtubule-stabilizing protein tau into insoluble fibrillar aggregates hold considerable promise for the prevention and/or treatment of neurodegenerative tauopathies such as Alzheimer's disease. Because tauopathies are characterized by amyloidosis that is restricted to the central nervous system (CNS), plausible candidate compounds for in vivo evaluation must both prevent tau fibrillization and achieve significant brain levels. Recently, we reported the discovery of the aminothienopyridazine (ATPZ) class of tau aggregation inhibitors and now describe a series of new analogues that are both effective inhibitors of tau fibrillization and display significant brain-to-plasma exposure ratios after administration to mice. Further, two of the most promising examples, 15 and 16, were found to reach significant brain exposure levels following oral administration. Taken together, these results suggest that examples from the ATPZ class hold promise as candidates for in vivo efficacy studies in animal models of neurodegenerative tauopathies.
authors.affiliation: Department of Chemistry, School of Arts and Sciences, University of Pennsylvania, 231 South 34th Street, Philadelphia, Pennsylvania 19104-6323, USA. bcarlo@sas.upenn.edu
authors.forename: Carlo
authors.initials: C
authors.lastname: Ballatore
authors.forename: Kurt R
authors.initials: KR
authors.lastname: Brunden
authors.forename: Francesco
authors.initials: F
authors.lastname: Piscitelli
authors.forename: Michael J
authors.initials: MJ
authors.lastname: James
authors.forename: Alex
authors.initials: A
authors.lastname: Crowe
authors.forename: Yuemang
authors.initials: Y
authors.lastname: Yao
authors.forename: Edward
authors.initials: E
authors.lastname: Hyde
authors.forename: John Q
authors.initials: JQ
authors.lastname: Trojanowski
authors.forename: Virginia M-Y
authors.initials: VM
authors.lastname: Lee
authors.forename: Amos B
authors.initials: AB
authors.lastname: Smith
mesh_terms: D000284:Administration, Oral; D000818:Animals; D001682:Biological Availability; D001812:Blood-Brain Barrier / Q000378:metabolism*; D055808:Drug Discovery; D051379:Mice; D055503:Protein Multimerization / Q000187:drug effects; D011724:Pyridazines / Q000493:pharmacokinetics*; D024801:Tauopathies / Q000188:drug therapy* / Q000517:prevention & control; D016875:tau Proteins / Q000187:drug effects*
chemical_list: D011724:Pyridazines; D016875:tau Proteins
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