The tissue distribution of a drug can have significant impact on both its efficacy and safety. As a consequence,
selective tissue targeting has become an attractive approach for optimizing the window between efficacy and safety for
drug targets that are ubiquitously expressed and important in key physiological processes. Given the liver’s key role in
metabolic regulation and the fact that it is the principal tissue affected by diseases such as hepatitis B and C viruses as
well as hepatocellular carcinoma, designing drugs with hepatoselective distribution profiles is an important strategy in developing
safe cardiovascular, metabolic, antiviral and oncology drug candidates.
In this paper, we analyze a diverse set of compounds from four different projects within Pfizer that specifically pursued
liver targeting strategies. A number of key in vitro and in vivo ADME endpoints were collected including in vivo tissue
exposure, oral bioavailability, clearance in preclinical species and in vitro hepatic OATP uptake, in vitro rat liver microsomal
stability, permeability, solubility, logD, and others. From this analysis, we determined a set of general structureliver-
selectivity guides for designing orally bioavailable, liver-targeted candidates using liver specific OATP transporters.
The guidelines have been formulated using straightforward molecular descriptors and in vitro properties that medicinal
chemists routinely optimize.
Our analysis emphasizes the need to focus on a chemical space with balanced lipophilicity, high aqueous solubility and
low passive permeability in order to achieve the desired hepatoselectivity while maintaining fraction absorbed.