A significant proportion of drugs reaching the market exhibit non-equilibrium binding characteristics.[1] Intuitively, it is likely that this represents a significant enrichment in compounds of this type the proportion of such compounds entering development and so these compounds must have benefits with respect to attrition. This could be due to increased efficacy and / or reduced toxicity. However, the majority of them appear to have been discovered without knowledge of their kinetic behaviour at the time of compound selection and these properties were revealed later as they became of greater interest to the wider community and subject to more detailed studies.It is often stated that association and dissociation rates cannot be manipulated rationally during optimisation. This talk will cover some of the principles of attempting to do so, highlighted with literature examples and data generated through our ongoing collaborative research project �Kinetics for Drug Discovery� (K4DD).[2] From these examples, some general observations give rise to hypotheses that may be of general relevance to the manipulation of kinetics and to a more detailed understanding of the underlying processes driving these observations at a molecular level.1. Swinney, D. C. Biochemical mechanisms of new molecular entities (NMEs) approved by United States FDA during 2001-2004: mechanisms leading to optimal efficacy and safety. Current Topics in Medicinal Chemistry, 2006, 6, 461-4782. http://www.k4dd.eu/

Medicinal chemistry optimisation of binding kinetics

248th National Meeting (2014)

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