title: Substituted 2H-isoquinolin-1-ones as potent Rho-kinase inhibitors: part 3, aryl substituted pyrrolidines.
abstract: The discovery and SAR of a series of beta-aryl substituted pyrrolidine 2H-isoquinolin-1-one inhibitors of Rho-kinase (ROCK) derived from 2 is herein described. SAR studies have shown that aryl groups in the beta-position are optimal for potency. Our efforts focused on improving the ROCK potency of this isoquinolone class of inhibitors which led to the identification of pyrrolidine 32 which demonstrated a 10-fold improvement in aortic ring (AR) potency over 2.
authors.affiliation: Department of Medicinal Chemistry, Boehringer-Ingelheim Pharmaceuticals, Inc., Ridgefield, CT 06877-0368, USA. todd.bosanac@boehringer-ingelheim.com
authors.forename: Todd
authors.initials: T
authors.lastname: Bosanac
authors.forename: Eugene R
authors.initials: ER
authors.lastname: Hickey
authors.forename: John
authors.initials: J
authors.lastname: Ginn
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: Alan
authors.initials: A
authors.lastname: Olague
authors.forename: Sabine
authors.initials: S
authors.lastname: Schlyer
authors.forename: Erick R R
authors.initials: ER
authors.lastname: Young
mesh_terms: D000818:Animals; D001011:Aorta / Q000187:drug effects; D018360:Crystallography, X-Ray; D015195:Drug Design; D006973:Hypertension / Q000188:drug therapy; D020128:Inhibitory Concentration 50; D007546:Isoquinolines / Q000737:chemistry* / Q000494:pharmacology; D015394:Molecular Structure; D047428:Protein Kinase Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D011759:Pyrrolidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D051381:Rats; D013329:Structure-Activity Relationship; D054460:rho-Associated Kinases / Q000037:antagonists & inhibitors*
chemical_list: D007546:Isoquinolines; D047428:Protein Kinase Inhibitors; D011759:Pyrrolidines; D054460:rho-Associated Kinases