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This article discusses the design and synthesis of novel 8-(azaindolyl)-benzoazepinones as potent and selective ROCK inhibitors. Through a core-hopping strategy and virtual screening workflow, potent inhibitors were identified by replacing the central core with a benzoazepinone ring. Compound 15 showed sub-nanomolar potencies in biochemical and cellular assays, along with remarkable selectivity over PKA. HDX studies supported the binding mode of compound 15 and highlighted the importance of specific ROCK peptide segments in driving ligand selectivity.
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 15 but also confirmed the crucial role of specific ROCK peptide segments in driving ligand selectivity.
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