Substituted 2H-isoquinolin-1-one as potent Rho-Kinase inhibitors. Part 1: Hit-to-lead account.
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.
Wu
Frank
F
Department of Medicinal Chemistry, Boehringer Ingelheim Pharmaceuticals, Inc., 900 Ridgebury Rd., Ridgefield, CT 06877, USA. frank.wu@boehringer-ingelheim.com
Büttner
Frank H
FH
Chen
Rhonda
R
Hickey
Eugene
E
Jakes
Scott
S
Kaplita
Paul
P
Kashem
Mohammed A
MA
Kerr
Steven
S
Kugler
Stanley
S
Paw
Zofia
Z
Prokopowicz
Anthony
A
Shih
Cheng-Kon
CK
Snow
Roger
R
Young
Erick
E
Cywin
Charles L
CL
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*
D000959:Antihypertensive Agents; D007546:Isoquinolines; D047428:Protein Kinase Inhibitors; D054460:rho-Associated Kinases