التفاصيل البيبلوغرافية
| العنوان: |
Discovery of Potent and Brain-Penetrant Tau Tubulin Kinase 1 (TTBK1) Inhibitors that Lower Tau Phosphorylation In Vivo |
| المؤلفون: |
Tamara Halkina (2379208), Jaclyn L. Henderson (2102971), Edward Y. Lin (10744817), Martin K. Himmelbauer (8463675), J. Howard Jones (2684047), Marta Nevalainen (1342470), Jun Feng (116162), Kristopher King (8042468), Michael Rooney (1601641), Joshua L. Johnson (1914394), Douglas J. Marcotte (8042471), Jayanth V. Chodaparambil (10744820), P. Rajesh Kumar (10744823), Thomas A. Patterson (10744826), Paramasivam Murugan (8042474), Eli Schuman (1960426), LaiYee Wong (10744829), Thomas Hesson (8042480), Sarah Lamore (10744832), Channa Bao (8681433), Michael Calhoun (6966182), Hannah Certo (10744835), Brenda Amaral (7521905), Gregory M. Dillon (8681430), Rab Gilfillan (8042486), Felix Gonzalez-Lopez de Turiso (8042489) |
| سنة النشر: |
2021 |
| المجموعة: |
Smithsonian Institution: Digital Repository |
| مصطلحات موضوعية: |
Biochemistry, Medicine, Cell Biology, Pharmacology, Biotechnology, Immunology, Biological Sciences not elsewhere classified, Chemical Sciences not elsewhere classified, vivo proof, TTBK inhibitor, disease-relevant Ser 422 epitope, kinase domain, pharmacology studies, 315 nM, azaindazole TTBK 1 inhibitors, mouse hypothermia, tau phosphorylation, Vivo Structural analysis, CNS penetration, TTBK 1, cell IC 50, Brain-Penetrant Tau Tubulin Kinase 1, NIK inhibitor 3, 571 nM, Systematic optimization, novel class |
| الوصف: |
Structural analysis of the known NIK inhibitor 3 bound to the kinase domain of TTBK1 led to the design and synthesis of a novel class of azaindazole TTBK1 inhibitors exemplified by 8 (cell IC 50 : 571 nM). Systematic optimization of this series of analogs led to the discovery of 31 , a potent (cell IC 50 : 315 nM) and selective TTBK inhibitor with suitable CNS penetration (rat K p,uu : 0.32) for in vivo proof of pharmacology studies. The ability of 31 to inhibit tau phosphorylation at the disease-relevant Ser 422 epitope was demonstrated in both a mouse hypothermia and a rat developmental model and provided evidence that modulation of this target may be relevant in the treatment of Alzheimer’s disease and other tauopathies. |
| نوع الوثيقة: |
dataset |
| اللغة: |
unknown |
| Relation: |
https://figshare.com/articles/dataset/Discovery_of_Potent_and_Brain-Penetrant_Tau_Tubulin_Kinase_1_TTBK1_Inhibitors_that_Lower_Tau_Phosphorylation_In_Vivo/14535560 |
| DOI: |
10.1021/acs.jmedchem.1c00382.s002 |
| الاتاحة: |
https://doi.org/10.1021/acs.jmedchem.1c00382.s002 |
| Rights: |
CC BY-NC 4.0 |
| رقم الانضمام: |
edsbas.287DD869 |
| قاعدة البيانات: |
BASE |