title: Substituted 2H-isoquinolin-1-ones as potent Rho-kinase inhibitors: part 2, optimization for blood pressure reduction in spontaneously hypertensive rats.
abstract: Phenylglycine substituted isoquinolones 1 and 2 have previously been described as potent dual ROCK1/ROCK2 inhibitors. Here we describe the further SAR of this series to improve metabolic stability and rat oral exposure. Piperidine analog 20 which demonstrates sustained blood pressure normalization in an SHR blood pressure reduction model was identified through this effort.
authors.affiliation: Department of Medicinal Chemistry, Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, CT 06877, USA. john.Ginn@boehringer-ingelheim.com
authors.forename: John D
authors.initials: JD
authors.lastname: Ginn
authors.forename: Todd
authors.initials: T
authors.lastname: Bosanac
authors.forename: Rhonda
authors.initials: R
authors.lastname: Chen
authors.forename: Charles
authors.initials: C
authors.lastname: Cywin
authors.forename: Eugene
authors.initials: E
authors.lastname: Hickey
authors.forename: Mohammed
authors.initials: M
authors.lastname: Kashem
authors.forename: Steven
authors.initials: S
authors.lastname: Kerr
authors.forename: Stanley
authors.initials: S
authors.lastname: Kugler
authors.forename: Xiang
authors.initials: X
authors.lastname: Li
authors.forename: Anthony
authors.initials: A
authors.lastname: Prokopowicz
authors.forename: Sabine
authors.initials: S
authors.lastname: Schlyer
authors.forename: James D
authors.initials: JD
authors.lastname: Smith
authors.forename: Michael R
authors.initials: MR
authors.lastname: Turner
authors.forename: Frank
authors.initials: F
authors.lastname: Wu
authors.forename: Erick R R
authors.initials: ER
authors.lastname: Young
mesh_terms: D000818:Animals; D001794:Blood Pressure / Q000187:drug effects*; D007546:Isoquinolines / Q000737:chemistry / Q000494:pharmacology*; D008958:Models, Molecular; D047428:Protein Kinase Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D011918:Rats, Inbred SHR; D013329:Structure-Activity Relationship; D054460:rho-Associated Kinases / Q000037:antagonists & inhibitors*
chemical_list: D007546:Isoquinolines; D047428:Protein Kinase Inhibitors; D054460:rho-Associated Kinases