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J Med Chem. 2015 Jun 25;58(12):5028-37. doi: 10.1021/acs.jmedchem.5b00424. Epub 2015 Jun 12.

Design, Synthesis, and Structure-Activity Relationships of Pyridine-Based Rho Kinase (ROCK) Inhibitors.

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†Vertex Pharmaceuticals, Inc., 50 Northern Avenue, Boston, Massachusetts 02210, United States.
‡Vertex Pharmaceuticals, Inc., 11010 Torreyana Road, San Diego, California 92121, United States.


The Rho kinases (ROCK1 and ROCK2) are highly homologous serine/threonine kinases that act on substrates associated with cellular motility, morphology, and contraction and are of therapeutic interest in diseases associated with cellular migration and contraction, such as hypertension, glaucoma, and erectile dysfunction. Beginning with compound 4, an inhibitor of ROCK1 identified through high-throughput screening, systematic exploration of SAR, and application of structure-based design, led to potent and selective ROCK inhibitors. Compound 37 represents significant improvements in inhibition potency, kinase selectivity, and CYP inhibition and possesses pharmacokinetics suitable for in vivo experimentation.

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