Substituted 2H-isoquinolin-1-one as potent Rho-Kinase inhibitors. Part 1: Hit-to-lead account

Frank Wu; Frank H Büttner; Rhonda Chen; Eugene Hickey; Scott Jakes; Paul Kaplita; Mohammed A Kashem; Steven Kerr; Stanley Kugler; Zofia Paw; Anthony Prokopowicz; Cheng-Kon Shih; Roger Snow; Erick Young; Charles L Cywin

doi:10.1016/j.bmcl.2010.04.070

Substituted 2H-isoquinolin-1-one as potent Rho-Kinase inhibitors. Part 1: Hit-to-lead account

Bioorg Med Chem Lett. 2010 Jun 1;20(11):3235-9. doi: 10.1016/j.bmcl.2010.04.070. Epub 2010 Apr 22.

Authors

Frank Wu¹, Frank H Büttner, Rhonda Chen, Eugene Hickey, Scott Jakes, Paul Kaplita, Mohammed A Kashem, Steven Kerr, Stanley Kugler, Zofia Paw, Anthony Prokopowicz, Cheng-Kon Shih, Roger Snow, Erick Young, Charles L Cywin

Affiliation

¹ Department of Medicinal Chemistry, Boehringer Ingelheim Pharmaceuticals, Inc., 900 Ridgebury Rd., Ridgefield, CT 06877, USA. frank.wu@boehringer-ingelheim.com

PMID: 20462760
DOI: 10.1016/j.bmcl.2010.04.070

Abstract

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.

MeSH terms

Animals
Antihypertensive Agents / chemistry
Antihypertensive Agents / pharmacology
Blood Pressure / drug effects
Crystallography, X-Ray
Drug Discovery
Isoquinolines / chemistry
Isoquinolines / pharmacology*
Models, Molecular
Protein Kinase Inhibitors / chemistry
Protein Kinase Inhibitors / pharmacology*
Rats
rho-Associated Kinases / antagonists & inhibitors*

Substances

Antihypertensive Agents
Isoquinolines
Protein Kinase Inhibitors
rho-Associated Kinases