Substituted 2H-isoquinolin-1-ones as potent Rho-kinase inhibitors: part 3, aryl substituted pyrrolidines

Todd Bosanac; Eugene R Hickey; John Ginn; Mohammed Kashem; Steven Kerr; Stanley Kugler; Xiang Li; Alan Olague; Sabine Schlyer; Erick R R Young

doi:10.1016/j.bmcl.2010.04.069

Substituted 2H-isoquinolin-1-ones as potent Rho-kinase inhibitors: part 3, aryl substituted pyrrolidines

Bioorg Med Chem Lett. 2010 Jun 15;20(12):3746-9. doi: 10.1016/j.bmcl.2010.04.069. Epub 2010 Apr 21.

Authors

Todd Bosanac¹, Eugene R Hickey, John Ginn, Mohammed Kashem, Steven Kerr, Stanley Kugler, Xiang Li, Alan Olague, Sabine Schlyer, Erick R R Young

Affiliation

¹ Department of Medicinal Chemistry, Boehringer-Ingelheim Pharmaceuticals, Inc., Ridgefield, CT 06877-0368, USA. todd.bosanac@boehringer-ingelheim.com

PMID: 20471253
DOI: 10.1016/j.bmcl.2010.04.069

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.

MeSH terms

Animals
Aorta / drug effects
Crystallography, X-Ray
Drug Design
Hypertension / drug therapy
Inhibitory Concentration 50
Isoquinolines / chemistry*
Isoquinolines / pharmacology
Molecular Structure
Protein Kinase Inhibitors / chemistry*
Protein Kinase Inhibitors / pharmacology
Pyrrolidines / chemical synthesis*
Pyrrolidines / chemistry
Pyrrolidines / pharmacology
Rats
Structure-Activity Relationship
rho-Associated Kinases / antagonists & inhibitors*

Substances

Isoquinolines
Protein Kinase Inhibitors
Pyrrolidines
rho-Associated Kinases