Discovery of Brain-Penetrant, Orally Bioavailable Aminothienopyridazine Inhibitors of Tau Aggregation

被引:44
作者
Ballatore, Carlo [1 ,2 ]
Brunden, Kurt R. [2 ]
Piscitelli, Francesco [1 ]
James, Michael J. [2 ]
Crowe, Alex [2 ]
Yao, Yuemang [2 ]
Hyde, Edward [2 ]
Trojanowski, John Q. [2 ]
Lee, Virginia M. -Y. [2 ]
Smith, Amos B., III [1 ]
机构
[1] Univ Penn, Sch Arts & Sci, Dept Chem, Philadelphia, PA 19104 USA
[2] Univ Penn, Inst Aging, Ctr Neurodegenerat Dis Res, Philadelphia, PA 19104 USA
关键词
PAIRED HELICAL FILAMENTS; ALZHEIMERS-DISEASE; CELL MODELS; IN-VITRO; NEURODEGENERATION; PHENOTHIAZINES; TAUOPATHIES; IMPAIRMENTS; DERIVATIVES;
D O I
10.1021/jm100138f
中图分类号
R914 [药物化学];
学科分类号
100701 ;
摘要
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.
引用
收藏
页码:3739 / 3747
页数:9
相关论文
共 31 条
[1]   Tau-mediated neurodegeneration in Alzheimer's disease and related disorders [J].
Ballatore, Carlo ;
Lee, Virginia M. -Y. ;
Trojanowski, John Q. .
NATURE REVIEWS NEUROSCIENCE, 2007, 8 (09) :663-672
[2]  
Brunden KR, 2008, J ALZHEIMERS DIS, V14, P393
[3]   Tau-directed drug discovery for Alzheimer's disease and related tauopathies: A focus on tau assembly inhibitors [J].
Brunden, Kurt R. ;
Ballatore, Carlo ;
Crowe, Alex ;
Smith, Amos B., III ;
Lee, Virginia M-Y ;
Trojanowski, John Q. .
EXPERIMENTAL NEUROLOGY, 2010, 223 (02) :304-310
[4]   Advances in tau-focused drug discovery for Alzheimer's disease and related tauopathies [J].
Brunden, Kurt R. ;
Trojanowski, John Q. ;
Lee, Virginia M. -Y. .
NATURE REVIEWS DRUG DISCOVERY, 2009, 8 (10) :783-793
[5]   Rhodanine-based tau aggregation inhibitors in cell models of tauopathy [J].
Bulic, Bruno ;
Pickhardt, Marcus ;
Khlistunova, Inna ;
Biernat, Jacek ;
Mandelkow, Eva-Maria ;
Mandelkow, Eckhard ;
Waldmann, Herbert .
ANGEWANDTE CHEMIE-INTERNATIONAL EDITION, 2007, 46 (48) :9215-9219
[6]   Structure-Activity Relationship of Cyanine Tau Aggregation Inhibitors [J].
Chang, Edward ;
Congdon, Erin E. ;
Honson, Nicolette S. ;
Duff, Karen E. ;
Kuret, Jeff .
JOURNAL OF MEDICINAL CHEMISTRY, 2009, 52 (11) :3539-3547
[7]   Ligand-dependent inhibition and reversal of tau filament formation [J].
Chirita, C ;
Necula, M ;
Kuret, J .
BIOCHEMISTRY, 2004, 43 (10) :2879-2887
[8]   Nucleation-dependent tau filament formation - The importance of dimerization and an estimation of elementary rate constants [J].
Congdon, Erin E. ;
Kim, Sohee ;
Bonchak, Jonathan ;
Songrug, Tanakorn ;
Matzavinos, Anastasios ;
Kuret, Jeff .
JOURNAL OF BIOLOGICAL CHEMISTRY, 2008, 283 (20) :13806-13816
[9]   High throughput screening for small molecule inhibitors of heparin-induced tau fibril formation [J].
Crowe, Alex ;
Ballatore, Carlo ;
Hyde, Edward ;
Trojanowski, John Q. ;
Lee, Virginia M. -Y. .
BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS, 2007, 358 (01) :1-6
[10]   Identification of Aminothienopyridazine Inhibitors of Tau Assembly by Quantitative High-Throughput Screening [J].
Crowe, Alex ;
Huang, Wenwei ;
Ballatore, Carlo ;
Johnson, Ronald L. ;
Hogan, Anne-Marie L. ;
Huang, Ruili ;
Wichterman, Jennifer ;
McCoy, Joshua ;
Huryn, Donna ;
Auld, Douglas S. ;
Smith, Amos B., III ;
Inglese, James ;
Trojanowski, John Q. ;
Austin, Christopher P. ;
Brunden, Kurt R. ;
Lee, Virginia M. -Y. .
BIOCHEMISTRY, 2009, 48 (32) :7732-7745