Profiling lead optimization

Van de Waterbeemd, H. Property-based lead optimization. In Biological and Physicochemical Profiling in Drug Research, Testa, B., Kramer, S. D., Wunderli-Allenspach, H., Folkers, G. (eds.), VHCA, Zurich and Wiley-VCH, Weinheim, 2006, pp. 25-45. 

With more limited PK support, an initial PK profile for a lead compound may be all that is available. This profile identifies issues that need to be solved during lead optimization. 

An early identification of the best leads is critical, and systematic biological profiling, as with Cerep BioPrint , enables this progress to a great extent. Experience with using this approach in a major pharmaceutical company (Pfizer) has confirmed this. One component of the issue can be stated that it is better to identify the best (not just potency) lead series than to try and find the best candidate from a possibly suboptimal series, which can happen at late stages of lead optimization, where it is very difficult to make major changes to the lead series chemistry. 

The paradigm shift from critical activities from later drug development to earlier discovery phases some years ago has effectively led to a change in lead optimization and added a new dimension of complexity, while it is envisioned that from a multidimensional, data-driven process more suitable candidates in accord with the therapeutic target product profiles may emerge for the treatment of currently unmet medical needs. 

Arrays of biological data can form the basis for uniquely informative molecular descriptors. By defining the relationships between compounds using biological descriptors (in vitro profiles) in addition to chemical structures, medicinal chemists are given new perspectives to support lead optimization. 

A positive result from a bacterial reporter assay would lower the ranking of the compound for development. The compound file should be aimotated with an alert for a confirmatory in vitro test (if the compound remains hve), in this case it might be a screening Ames at a later stage. There should also be a second alert to the lead optimization chemists. A third alert should still notify the genotoxicity safety assessment team that the compound is a priority for mechanistic investigation if the series continues, with the associated need for coordination of in vivo studies, this would be a lower priority than an Ames profiling positive. 

At lead selection, after which typically more chemistry effort is invested, the selected compounds can be profiled in a broader (secondary) panel of assays, hopefully confirming the selective nature of the leads. If this is the case, spot checking in the primary panel through the optimization phase may be sufficient to ensure selectivity is retained while the required potency at the primary target is achieved. If the selected leads are still rather promiscuous, or certain individual unwanted liabilities remain, these should be monitored by testing in the primary panel (or in additional individual assays) and improved upon during lead optimization. Tfie broader panel can then be applied again to the selected development candidates for a final check and these may even be extended further to additional specialized panels for added security. 

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