Lead Optimisation & Drug-Induced Cardiotoxicity
Scendea Authors:
Dr Erik Doevendans, Ellen Wilkinson
ERBC Authors:
Pascal Champeroux, PhD
Raafat Fares, PhD, dABT, dSP, ERT
The drug discovery and development process that takes a chemical compound from initial lead selection to preclinical evaluation and ultimately the clinic is not necessarily a linear one.
Initially, potential drug candidates are evaluated through a multi-step screening process in order to select lead compounds, ‘hits’, that demonstrate on-target activity with minimal toxicity potential. The physical properties of these hits are also characterised at this stage including their solubility, stability and purity. However, once lead compounds are identified, there remains a need to optimise their characteristics including target selectivity, biological activity and potency. This is termed ‘lead optimisation’. Developers should also use the opportunity to minimise the toxicity potential of their lead compounds and prevent down-stream delays or halts to development based on safety concerns. Lead optimisation plays a critical role in drug development as a selected lead may not necessarily be the optimal lead. In the case that during safety pharmacology and/or toxicology studies it appears that a sub-optimal lead was selected, developers should consider taking one step back and optimise their compound before proceeding with development. Ultimately, lead optimisation will further de-risk the drug development program.
In this paper we discuss the value of lead optimisation with a specific focus on how developers can approach minimising drug-induced cardiotoxicity potential. Additionally, we discuss the regulatory guidelines to consider and the need for new methods in evaluating functional cardiotoxicity.