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We report the characterization of potent and selective ROCK inhibitors identified through a core-hopping strategy. A virtual screening workflow, combining ligand- and structure-based methods, was applied on a known series of ROCK inhibitors bearing an acetamido-thiazole scaffold. The most promising replacement of the central core was represented by a benzoazepinone ring, which was selected as a starting point for a subsequent chemical exploration. The overall design approach exploited previous SARs available for congeneric series and crystallographic information to optimize the hinge-binding group as well as the terminal aromatic moiety interacting with the glycine-rich loop. The introduction of elongated and flexible charged groups led to compound 15, which exhibited sub-nanomolar potencies in biochemical and cellular assays, as well as a remarkable selectivity over PKA. HDX studies not only supported the postulated binding mode of compound 15but also confirmed the crucial role of specific ROCK peptide segments in driving ligand selectivity.