The state of the art in secondary pharmacology and its impact on the safety of new medicines.

Secondary pharmacology screening of investigational small-molecule drugs for potentially adverse off-target activities has become standard practice in pharmaceutical research and development, and regulatory agencies are increasingly requesting data on activity against targets with recognized adverse effect relationships. However, the screening strategies and target panels used by pharmaceutical companies may vary substantially. To help identify commonalities and differences, as well as to highlight opportunities for further optimization of secondary pharmacology assessment, we conducted a broad-ranging survey across 18 companies under the auspices of the DruSafe leadership group of the International Consortium for Innovation and Quality in Pharmaceutical Development.

Time for a Fully Integrated Nonclinical-Clinical Risk Assessment to Streamline QT Prolongation Liability Determinations: A Pharma Industry Perspective.

Defining an appropriate and efficient assessment of drug-induced corrected QT interval (QTc) prolongation (a surrogate marker of torsades de pointes arrhythmia) remains a concern of drug developers and regulators worldwide. In use for over 15 years, the nonclinical International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use (ICH) S7B and clinical ICH E14 guidances describe three core assays (S7B: in vitro hERG current & in vivo QTc studies; E14: thorough QT study) that are used to assess the potential of drugs to cause delayed ventricular repolarization. Incorporating these assays during nonclinical or human testing of novel compounds has led to a low prevalence of QTc-prolonging drugs in clinical trials and no new drugs having been removed from the marketplace due to unexpected QTc prolongation.

In vitro secondary pharmacological profiling: An IQ-DruSafe industry survey on current practices.

Introduction: In 2015, IQ DruSafe conducted a survey of its membership to identify industry practices related to in vitro off target pharmacological profiling of small molecules.

Methods: An anonymous survey of 20 questions was submitted to IQ-DruSafe representatives. Questions were designed to explore screening strategies, methods employed and experience of regulatory interactions related to in vitro secondary pharmacology profiling.

Screening technologies for ion channel drug discovery.

For every movement, heartbeat and thought, ion channels need to open and close. It is therefore not surprising that their malfunctioning leads to serious diseases. Currently, only approximately 10% of drugs, with a market value in excess of US$10 billion, act on ion channels.

Development of an improved IP(1) assay for the characterization of 5-HT(2C) receptor ligands.

The 5-hydroxytryptamine 2C (5-HT(2C)) receptor is a member of the serotonin 5-HT(2) subfamily of G-protein-coupled receptors signaling predominantly via the phospholipase C (PLC) pathway. Stimulation of phosphoinositide (PI) hydrolysis upon 5-HT(2C) receptor activation is traditionally assessed by measuring inositol monophosphate (IP(1)) using time-consuming and labor-intensive anion exchange radioactive assays. In this study, we have developed and optimized a cellular IP(1) assay using homogeneous time-resolved fluorescence (HTRF), a fluorescence resonance energy transfer (FRET)-based technology (Cisbio; Gif sur Yvette, France).

Ion channel screening.

Ion channels are attractive targets for drug discovery with recent estimates indicating that voltage and ligand-gated channels account for the third and fourth largest gene families represented in company portfolios after the G protein coupled and nuclear hormone receptor families. A historical limitation on ion channel targeted drug discovery in the form of the extremely low throughput nature of the gold standard assay for assessing functional activity, patch clamp electrophysiology in mammalian cells, has been overcome by the implementation of multi-well plate format cell-based screening strategies for ion channels. These have taken advantage of various approaches to monitor ion flux or membrane potential using radioactive, non-radioactive, spectroscopic and fluorescence measurements and have significantly impacted both high-throughput screening and lead optimization efforts.

Functional screening of α7 nicotinic receptor ligands.

Background: The α7 nicotinic acetylcholine receptor, a ligand-gated ion channel, is an attractive drug discovery target in schizophrenia and Alzheimer's disease.

Objective: We have evaluated the various approaches to discovering ligands targeting the α7 nicotinic receptor to define the current paradigm driving drug discovery efforts in this area.

Methods: Assays using functional read-outs as a consequence of α7 nicotinic receptor activation have been reviewed.

High-throughput electrophysiology: an emerging paradigm for ion-channel screening and physiology.

Ion channels represent highly attractive targets for drug discovery and are implicated in a diverse range of disorders, in particular in the central nervous and cardiovascular systems. Moreover, assessment of cardiac ion-channel activity of new chemical entities is now an integral component of drug discovery programmes to assess potential for cardiovascular side effects. Despite their attractiveness as drug discovery targets ion channels remain an under-exploited target class, which is in large part due to the labour-intensive and low-throughput nature of patch-clamp electrophysiology.