Design and synthesis of novel 8-(azaindolyl)-benzoazepinones as potent and selective ROCK inhibitors.

ABSTRACT: 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 potenci

SUBMITTER: Pala D 

PROVIDER: S-EPMC11406669 | biostudies-literature | 2024 Sep

REPOSITORIES: biostudies-literature