Bibliographic Details
| Title: |
Discovery of Potent and Brain-Penetrant Tau Tubulin Kinase 1 (TTBK1) Inhibitors that Lower Tau Phosphorylation In Vivo |
| Authors: |
Halkina, Tamara, Henderson, Jaclyn L., Lin, Edward Y., Himmelbauer, Martin K., Jones, J. Howard, Nevalainen, Marta, Feng, Jun, King, Kristopher, Rooney, Michael, Johnson, Joshua L., Marcotte, Douglas J., Chodaparambil, Jayanth V., Kumar, P. Rajesh, Patterson, Thomas A., Murugan, Paramasivam, Schuman, Eli, Wong, LaiYee, Hesson, Thomas, Lamore, Sarah, Bao, Channa, Calhoun, Michael, Certo, Hannah, Amaral, Brenda, Dillon, Gregory M., Gilfillan, Rab, de Turiso, Felix Gonzalez-Lopez |
| Source: |
Journal of Medicinal Chemistry; 20210101, Issue: Preprints |
| Abstract: |
Structural analysis of the known NIK inhibitor 3bound to the kinase domain of TTBK1 led to the design and synthesis of a novel class of azaindazole TTBK1 inhibitors exemplified by 8(cell IC50: 571 nM). Systematic optimization of this series of analogs led to the discovery of 31, a potent (cell IC50: 315 nM) and selective TTBK inhibitor with suitable CNS penetration (rat Kp,uu: 0.32) for in vivo proof of pharmacology studies. The ability of 31to 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. |
| Database: |
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