Discovery of Potent and Brain-Penetrant Tau Tubulin Kinase 1 (TTBK1) Inhibitors that Lower Tau Phosphorylation In Vivo

Abstract

Structural analysis of the known NIK inhibitor <b>3</b> bound to the kinase domain of TTBK1 led to the design and synthesis of a novel class of azaindazole TTBK1 inhibitors exemplified by <b>8</b> (cell IC₅₀: 571 nM). Systematic optimization of this series of analogs led to the discovery of <b>31</b>, a potent (cell IC₅₀: 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 <b>31</b> 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.