The protein kinase NUAK1 has been implicated in various biological functions including cell adhesion, migration and proliferation. Genetic reduction of NUAK1 expression has notably been shown to lower total levels of human tau in a tauopathy mouse model, identifying this kinase as a potential therapeutic target for neurodegenerative disease. In this paper, we describe improvement of the NUAK1 potency, kinase-selectivity and pharmacokinetic properties of the brain-penetrant but unselective CDK4/CDK6/NUAK1 inhibitor ON123300. Through a scaffold-optimization approach we have identified different chemotypes delivering NUAK1 inhibition with improved potency and selectivity over CDK kinases compared with ON123300. We present ADME profiling and in vivo pharmacokinetic data for these compounds.