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

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 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 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.

Toward homogeneous erythropoietin: non-NCL-based chemical synthesis of the Gln78-Arg166 glycopeptide domain.

Single erythropoietin (EPO) glycoforms with defined mature oligosaccharide structures and amino acid sequences are essential to elucidate the molecular mechanisms by which carbohydrates exert various physiological and metabolic functions and to explore the possible links between carbohydrates and the prevention or management of diseases. To demonstrate that it is possible to generate EPO even without recourse to cysteine-based native chemical ligation, a concise synthesis of the partially protected EPO fragment (78-166) bearing fully mature N- and O-glycans is described.