Amber Y.S. Balazs, Director, US Analytical, Structural, and Chromatography (ASC) Team, Early Oncology Chemistry NMR Specialist, AstraZeneca
Recognition that oral absorption of drugs can be related to molecular structural features and intrinsic physical chemistry properties, namely the Lipinski ‘Rule of Five’ and subsequent ‘drug-likeness’ variants, have provided powerful models in drug discovery for triaging design ideas. Oral drugs that have advanced to clinical development and regulatory approval, despite one or more violations of traditional predictive guidelines, have raised doubts and questions regarding the usefulness of these models in drug discovery. To see if trends could be observed across Ro5 violations in orally absorbed drugs, we experimentally examined Structure-Property Relationships of clinical candidates and marketed drugs. We measured free ligand solution conformations and dynamics for a set of 15 bRo5 compounds. In addition, we explored the experimental ‘drug-likeness’ space using experimental structural descriptors for hydrogen bond donor and acceptor counts, and number of rotatable bonds, as well as chromatographic measurements of lipophilicity (chromLogD) and exposed polar surface area (ePSA). The resultant hypothesis was tested across a set of approximately 100 compounds providing important insights leading to a more accurate prediction of physicochemical property drivers for oral absorption.