title: Design, Synthesis, and Structure-Activity Relationships of Pyridine-Based Rho Kinase (ROCK) Inhibitors.
abstract: 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.
authors.affiliation: †Vertex Pharmaceuticals, Inc., 50 Northern Avenue, Boston, Massachusetts 02210, United States.
authors.forename: Jeremy
authors.initials: J
authors.lastname: Green
authors.affiliation: †Vertex Pharmaceuticals, Inc., 50 Northern Avenue, Boston, Massachusetts 02210, United States.
authors.forename: Jingrong
authors.initials: J
authors.lastname: Cao
authors.affiliation: †Vertex Pharmaceuticals, Inc., 50 Northern Avenue, Boston, Massachusetts 02210, United States.
authors.forename: Upul K
authors.initials: UK
authors.lastname: Bandarage
authors.affiliation: †Vertex Pharmaceuticals, Inc., 50 Northern Avenue, Boston, Massachusetts 02210, United States.
authors.forename: Huai
authors.initials: H
authors.lastname: Gao
authors.affiliation: †Vertex Pharmaceuticals, Inc., 50 Northern Avenue, Boston, Massachusetts 02210, United States.
authors.forename: John
authors.initials: J
authors.lastname: Court
authors.affiliation: †Vertex Pharmaceuticals, Inc., 50 Northern Avenue, Boston, Massachusetts 02210, United States.
authors.forename: Craig
authors.initials: C
authors.lastname: Marhefka
authors.affiliation: †Vertex Pharmaceuticals, Inc., 50 Northern Avenue, Boston, Massachusetts 02210, United States.
authors.forename: Marc
authors.initials: M
authors.lastname: Jacobs
authors.affiliation: †Vertex Pharmaceuticals, Inc., 50 Northern Avenue, Boston, Massachusetts 02210, United States.
authors.forename: Paul
authors.initials: P
authors.lastname: Taslimi
authors.affiliation: †Vertex Pharmaceuticals, Inc., 50 Northern Avenue, Boston, Massachusetts 02210, United States.
authors.forename: David
authors.initials: D
authors.lastname: Newsome
authors.affiliation: †Vertex Pharmaceuticals, Inc., 50 Northern Avenue, Boston, Massachusetts 02210, United States.
authors.forename: Tomoko
authors.initials: T
authors.lastname: Nakayama
authors.affiliation: ‡Vertex Pharmaceuticals, Inc., 11010 Torreyana Road, San Diego, California 92121, United States.
authors.forename: Sundeep
authors.initials: S
authors.lastname: Shah
authors.affiliation: ‡Vertex Pharmaceuticals, Inc., 11010 Torreyana Road, San Diego, California 92121, United States.
authors.forename: Steve
authors.initials: S
authors.lastname: Rodems
mesh_terms: D006801:Humans; D062105:Molecular Docking Simulation; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D011725:Pyridines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D054460:rho-Associated Kinases / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism
chemical_list: D047428:Protein Kinase Inhibitors; D011725:Pyridines; C515851:ROCK1 protein, human; C515852:ROCK2 protein, human; D054460:rho-Associated Kinases