Substituted 2H-isoquinolin-1-ones as potent Rho-kinase inhibitors: part 2, optimization for blood pressure reduction in spontaneously hypertensive rats.
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.
Ginn
John D
JD
Department of Medicinal Chemistry, Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, CT 06877, USA. john.Ginn@boehringer-ingelheim.com
Bosanac
Todd
T
Chen
Rhonda
R
Cywin
Charles
C
Hickey
Eugene
E
Kashem
Mohammed
M
Kerr
Steven
S
Kugler
Stanley
S
Li
Xiang
X
Prokopowicz
Anthony
A
Schlyer
Sabine
S
Smith
James D
JD
Turner
Michael R
MR
Wu
Frank
F
Young
Erick R R
ER
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*
D007546:Isoquinolines; D047428:Protein Kinase Inhibitors; D054460:rho-Associated Kinases