The Impact of IKr Blockade on Medicinal Chemistry Programs

Title: The Impact of IKr Blockade on Medicinal Chemistry Programs

Volume: 8 Issue: 13

Author(s): Ian M. Bell and Mark T. Bilodeau

Affiliation:

Keywords: Blockade, ventricular arrhythmia, medicinal chemistry programs, antagonism, Class III antiarrhythmic agents, myocardial infarction

Abstract: Inhibition of the cardiac IKr current leads to prolongation of the QT interval and to a risk of ventricular arrhythmia. This activity has been observed for a wide range of small molecules and results from their binding to the hERG ion channel. The off-target inhibition of IKr presents a daunting challenge for many medicinal chemistry programs. This review article presents case studies that describe a rang of findings across several projects at Merck. The article begins with a review of findings from the original efforts to identify IKr blockers as antiarrhythmic therapeutics. A discussion follows of in vitro and in vivo assays that have been utilized for the assessment of IKr inhibition. General SAR rules that have been found to be useful guides for diminishing hERG activity in lead compounds are discussed and case studies are presented that illustrate specific observations. The case studies highlight how the issue of hERG antagonism was navigated on four distinct medicinal chemistry programs.

Cite this article as:

Bell M. Ian and Bilodeau T. Mark, The Impact of IKr Blockade on Medicinal Chemistry Programs, Current Topics in Medicinal Chemistry 2008; 8 (13) . https://dx.doi.org/10.2174/156802608785700034