The serine/threonine kinase SGK1 is an activator of the β-catenin pathway and a powerful stimulator of cartilage degradation that is found to be upregulated under genomic control in diseased osteoarthritic cartilage. Today no oral disease-modifying treatments are available and chronic treatment in this indication sets high requirements for the drug selectivity, pharmacokinetic and safety profile. We describe the preparation of a highly selective druglike 1H-pyrazolo[3,4-d]pyrimidine SGK1 inhibitor that matches both safety and pharmacokinetic requirements for oral dosing. Rational compound design was facilitated by a novel hSGK1 cocrystal structure and classic medicinal chemistry was applied to guide the chemical optimization of ADMET and selectivity profiles.