Substituted 2H-isoquinolin-1-ones as potent Rho-kinase inhibitors: part 3, aryl substituted pyrrolidines.
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.
Bosanac
Todd
T
Department of Medicinal Chemistry, Boehringer-Ingelheim Pharmaceuticals, Inc., Ridgefield, CT 06877-0368, USA. todd.bosanac@boehringer-ingelheim.com
Hickey
Eugene R
ER
Ginn
John
J
Kashem
Mohammed
M
Kerr
Steven
S
Kugler
Stanley
S
Li
Xiang
X
Olague
Alan
A
Schlyer
Sabine
S
Young
Erick R R
ER
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*
D007546:Isoquinolines; D047428:Protein Kinase Inhibitors; D011759:Pyrrolidines; D054460:rho-Associated Kinases