Identification of potent, highly constrained CGRP receptor antagonists.

A novel series of potent CGRP receptor antagonists containing a central quinoline ring constraint was identified. The combination of the quinoline constraint with a tricyclic benzimidazolinone left hand fragment produced an analog with picomolar potency (14, CGRP K(i)=23 pM). Further optimization of the tricycle produced a CGRP receptor antagonist that exhibited subnanomolar potency (19, CGRP K(i)=0.52 nM) and displayed a good pharmacokinetic profile in three preclinical species.

Role of hERG potassium channel assays in drug development.

Numerous structurally and functionally unrelated drugs block the hERG potassium channel. HERG channels are involved in cardiac action potential repolarization, and reduced function of hERG lengthens ventricular action potentials, prolongs the QT interval in an electrocardiogram, and increases the risk for potentially fatal ventricular arrhythmias. In order to reduce the risk of investing resources in a drug candidate that fails preclinical safety studies because of QT prolongation, it is important to screen compounds for activity on hERG channels early in the lead optimization process. A number of hERG assays are available, ranging from high throughput binding assays on stably expressed recombinant channels to very time consuming electrophysiological examinations in cardiac myocytes. Depending on the number of compounds to be tested, binding assays or functional assays measuring membrane potential or Rb(+) flux, combined with electrophysiology on a few compounds, can be used to efficiently develop the structure-function relationship of hERG interactions.

The impact of I(Kr) blockade on medicinal chemistry programs.

Inhibition of the cardiac I(Kr) 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 I(Kr) 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 I(Kr) blockers as antiarrhythmic therapeutics. A discussion follows of in vitro and in vivo assays that have been utilized for the assessment of I(Kr) 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.