Conclusion

The incorporation of "drug-like" criteria into the drug candidate selection process via a "gate-keeper" approach is certainly a first step in driving lead optimization toward the consideration of "drug-like" properties. However, the efficient integration of "drug-like" principles during the lead optimization process will require an interactive partnership between pharmaceutics, drug metabolism, toxicology and the Discovery team.

The concept of "drug delivery" during lead optimization should be expanded beyond in vivo oral exposure assessments to also include exposure of a compound to the intended target in an in vitro assay within a screening funnel. An appreciation of how physical chemical properties such as protein binding, solubility, permeability and surface activity may influence the readout of in vitro assays provides a perspective that can help to avoid ambiguous interpretation of data.

The enhancement of in vivo exposure following oral dosing can often be influenced through the use of various formulation and solubilization technologies. However, it is essential that the potential ramifications of applying these technologies during lead optimization are recognized and accepted by the team. In many cases, to carry these technologies well beyond the preclinical proof of concept studies may not be desirable. Therefore, while solubilization technologies can certainly be applied to overcome poor solubility, the preferred approach is and always will be to engineer out the poor solubility during the lead optimization phases when possible. When it isn't possible, then use of an enabling formulation should become an integral part of the screening process.

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