Qualitative pharmacology in a quantitative world: diminishing value in the drug discovery process

Preclinical characterization of new chemical entities (NCEs) in terms of efficacy, safety and their pharmacokinetic (PK), pharmacodynamic and pharmaceutical properties, is key to advancing appropriate compounds to clinical trials. The use of high throughput synthetic and screening methodologies has frequently led to NCE characterization becoming highly reductionistic, to the extent that compounds are often selected without adequate characterization. Classical, null hypothesis-based approaches involving the use of concentration/dose response curves and antagonists have been replaced by more qualitative approaches that limit NCE characterization. The return to a more integrated, hierarchical and pharmacologically driven approach will aid in ensuring that the NCEs advanced to clinical status are better understood, strengthening the process and predictivity of the translational approach in drug discovery.

► Drug discovery productivity has decreased. ► Characterization of new chemical entities has become increasingly qualitative. ► As a result inadequately characterized compounds are advanced to the clinic. ► A return to classical pharmacologically based approaches is necessary. ► This will strengthen translational predictivity by choosing better compounds.