Paul D. Leeson

TL;DR: Analysis of recent trends reveals that the physical properties of molecules that are currently being synthesized in leading drug discovery companies differ significantly from those of recently discovered oral drugs and compounds in clinical development.

TL;DR: The compilation and analysis of combined data on the attrition of drug candidates from AstraZeneca, Eli Lilly and Company, GlaxoSmithKline and Pfizer reaffirms that control of physicochemical properties during compound optimization is beneficial in identifying compounds of candidate drug quality and indicates for the first time a link between the physic biochemical properties of compounds and clinical failure due to safety issues.

TL;DR: Optimize ligand efficiency metrics based on both molecular mass and lipophilicity, when set in the context of the specific target, has the potential to ameliorate the inflation of these properties that has been observed in current medicinal chemistry practice, and to increase the quality of drug candidates.

TL;DR: The optimization of low-potency leads into drugs is often accompanied by an increase in molecular weight and lipophilicity, as a consequence of affinity enhancement, shown schematically by the distributions of M(r) for a leadlike library, oral drugs, and a typical combinatorial chemistry library.

TL;DR: Lead structures exhibit, on the average, less molecular complexity, are less hydrophobic, and less druglike (lower druglike scores), and this information should be used in the design of novel combinatorial libraries that are aimed at lead discovery.