Abstract
Nonclinical Toxicology During “Lead Optimization”.
The major deliverable from a “lead optimization” (LO) tox package will be a high-quality candidate compound, suitably characterized to enable judgment-based selection of clinical candidates destined for further development and preparation for initial clinical investigation. For small molecules, the LO phase of development typically represents the first opportunity to characterize the novel chemistry using an integrated approach that collectively scrutinizes a molecule’s overall “druggability,” with a focus on characterization of all the physical chemistry properties that may influence drug disposition, safety and tolerability, and dose prediction (with the underlying assumption that the hypothetical biological mechanism of action remains intact).
In keeping with the 3R principles, modern safety assessment continues to explore the potential risks and liabilities associated with the chemical structure via various predictive in silico screens that tackle both intrinsic toxicophore identification, in addition to structural similarity assessment of chemical moieties appearing in other structures with known adverse event profiles, and a battery of cell-based profiling assays that enable characterization of tolerability based on chemical properties, in addition to bespoke cell models that afford characterization of functional risk (e.g., induced pluripotent cell lines for different target organ systems). Collectively, these data are used to better inform investigators on the potential in vivo risks which may manifest in the preliminary multidose studies, which are designed to not only corroborate the in vitro predictive assessments but also identify the degree of monitorability (and subsequently, manageability) of on- and/or off-target toxicities associated with different drug exposures, in the context of a developable clinical dosing range.
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© 2017 American Association of Pharmaceutical Scientists
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Andrews, M.H., Reynolds, V.L. (2017). Lead Optimization, Preclinical Toxicology. In: Bhattachar, S., Morrison, J., Mudra, D., Bender, D. (eds) Translating Molecules into Medicines. AAPS Advances in the Pharmaceutical Sciences Series, vol 25. Springer, Cham. https://doi.org/10.1007/978-3-319-50042-3_8
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DOI: https://doi.org/10.1007/978-3-319-50042-3_8
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