Substituted 2H-isoquinolin-1-ones as potent Rho-kinase inhibitors: part 2, optimization for blood pressure reduction in spontaneously hypertensive rats

John D Ginn; Todd Bosanac; Rhonda Chen; Charles Cywin; Eugene Hickey; Mohammed Kashem; Steven Kerr; Stanley Kugler; Xiang Li; Anthony Prokopowicz 3rd; Sabine Schlyer; James D Smith; Michael R Turner; Frank Wu; Erick R R Young

doi:10.1016/j.bmcl.2010.07.014

Substituted 2H-isoquinolin-1-ones as potent Rho-kinase inhibitors: part 2, optimization for blood pressure reduction in spontaneously hypertensive rats

Bioorg Med Chem Lett. 2010 Sep 1;20(17):5153-6. doi: 10.1016/j.bmcl.2010.07.014. Epub 2010 Aug 1.

Authors

John D Ginn¹, Todd Bosanac, Rhonda Chen, Charles Cywin, Eugene Hickey, Mohammed Kashem, Steven Kerr, Stanley Kugler, Xiang Li, Anthony Prokopowicz 3rd, Sabine Schlyer, James D Smith, Michael R Turner, Frank Wu, Erick R R Young

Affiliation

¹ Department of Medicinal Chemistry, Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, CT 06877, USA. [email protected]

PMID: 20678931
DOI: 10.1016/j.bmcl.2010.07.014

Abstract

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.

MeSH terms

Animals
Blood Pressure / drug effects*
Isoquinolines / chemistry
Isoquinolines / pharmacology*
Models, Molecular
Protein Kinase Inhibitors / chemistry
Protein Kinase Inhibitors / pharmacology*
Rats
Rats, Inbred SHR
Structure-Activity Relationship
rho-Associated Kinases / antagonists & inhibitors*

Substances

Isoquinolines
Protein Kinase Inhibitors
rho-Associated Kinases