title: Substituted 2H-isoquinolin-1-one as potent Rho-Kinase inhibitors. Part 1: Hit-to-lead account.
abstract: Two closely related scaffolds were identified through an uHTS campaign as desirable starting points for the development of Rho-Kinase (ROCK) inhibitors. Here, we describe our hit-to-lead evaluation process which culminated in the rapid discovery of potent leads such as 22 which successfully demonstrated an early in vivo proof of concept for anti-hypertensive activity.
authors.affiliation: Department of Medicinal Chemistry, Boehringer Ingelheim Pharmaceuticals, Inc., 900 Ridgebury Rd., Ridgefield, CT 06877, USA. frank.wu@boehringer-ingelheim.com
authors.forename: Frank
authors.initials: F
authors.lastname: Wu
authors.forename: Frank H
authors.initials: FH
authors.lastname: Büttner
authors.forename: Rhonda
authors.initials: R
authors.lastname: Chen
authors.forename: Eugene
authors.initials: E
authors.lastname: Hickey
authors.forename: Scott
authors.initials: S
authors.lastname: Jakes
authors.forename: Paul
authors.initials: P
authors.lastname: Kaplita
authors.forename: Mohammed A
authors.initials: MA
authors.lastname: Kashem
authors.forename: Steven
authors.initials: S
authors.lastname: Kerr
authors.forename: Stanley
authors.initials: S
authors.lastname: Kugler
authors.forename: Zofia
authors.initials: Z
authors.lastname: Paw
authors.forename: Anthony
authors.initials: A
authors.lastname: Prokopowicz
authors.forename: Cheng-Kon
authors.initials: CK
authors.lastname: Shih
authors.forename: Roger
authors.initials: R
authors.lastname: Snow
authors.forename: Erick
authors.initials: E
authors.lastname: Young
authors.forename: Charles L
authors.initials: CL
authors.lastname: Cywin
mesh_terms: D000818:Animals; D000959:Antihypertensive Agents / Q000737:chemistry / Q000494:pharmacology; D001794:Blood Pressure / Q000187:drug effects; D018360:Crystallography, X-Ray; D055808:Drug Discovery; D007546:Isoquinolines / Q000737:chemistry / Q000494:pharmacology*; D008958:Models, Molecular; D047428:Protein Kinase Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D054460:rho-Associated Kinases / Q000037:antagonists & inhibitors*
chemical_list: D000959:Antihypertensive Agents; D007546:Isoquinolines; D047428:Protein Kinase Inhibitors; D054460:rho-Associated Kinases