Integrating the Impact of Lipophilicity on Potency and Pharmacokinetic Parameters Enables the Use of Diverse Chemical Space during Small Molecule Drug Optimization

• Published in: Journal of medicinal chemistry Vol. 63; no. 21; pp. 12156 - 12170
• Main Authors: Miller, Randy R, Madeira, Maria, Wood, Harold B, Geissler, Wayne M, Raab, Conrad E, Martin, Iain J
• Format: Journal Article
• Language: English
• Published: United States American Chemical Society 12-11-2020
• Subjects: Area Under Curve; Blood Proteins - chemistry; Blood Proteins - metabolism; Drug Design; Half-Life; Humans; Hydrophobic and Hydrophilic Interactions; Pharmaceutical Preparations - chemistry; Pharmaceutical Preparations - metabolism; Protein Binding; ROC Curve; Small Molecule Libraries - chemistry; Small Molecule Libraries - metabolism; Small Molecule Libraries - pharmacokinetics
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/acs.jmedchem.9b01813

Lipophilicity has a dominant effect on many parameters that determine unbound drug exposure as well as drug potency. Despite this, analysis of a large body of drug data indicates lipophilicity has no consistent directional impact on dose. This can be rationalized based on the interplay of the effects of lipophilicity on individual parameter values in pharmacokinetic equations. We believe this undermines the effectiveness of strategies that target specific ranges for drug parameters for which lipophilicity plays such a dominant role. As a result, our research organization no longer leverages the common approach of screening for low intrinsic clearance in vitro to target high unbound exposure in vivo. Instead, we advocate for approaches less biased to lipophilicity through optimization of key parameter ratios controlling dose. We believe this improves efficiency in drug discovery by enabling exploration of broad physicochemical space.