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Drug Discovery


Table 4: What does a kinetic profile deliver? PROFILE Fast on/Fast off


HOW DOES THE COMPOUND BEHAVE?


Rapidly reaches effective concentration at receptor, rapidly dissociates


Slow on/Slow off


Takes time to build to effective concentration at receptor, slow


dissociation once bound PROS


Low dose required for effect hence good therapeutic index. Could be preferable if bioavailability is poor


Long duration allows once daily dosing, stable effects between peak and trough; Long duration even if free drug is subject to rapid clearance


CONS


Duration is determined by clearance rate of free drug hence frequent dosing often required


Slow on-rate, if plasma concentration is low, may mean that drug never achieves sufficient receptor occupancy for efficacy


An ability to modulate on and off-rates would be particularly valuable where poor pharmacokinetics are observed. Where bioavailability is low, a high on rate is essential to get the drug on to the bind- ing site. Improving affinity by decreasing the off- rate will not help since dissociation rate is only important if there is a drug-target complex in the first place (in most cases, the drug will have to achieve some minimum receptor occupancy level to achieve efficacy). Contrarily, where the effec- tiveness of a drug series is compromised by rapid clearance, a compound with a very slow off-rate can still be efficacious, by maintaining receptor occupancy longer than the half life of the free drug would suggest. Decreasing the off-rate will be much more important than increasing the affinity (eg by increasing the on-rate) in this circumstance. Slow functional reversibility is associated with long lasting in vivo efficacy, whereas the efficacy of compounds with rapid reversibility is determined by their pharmacokinetics. To summarise, there is no ‘best ‘ kinetic profile; it depends on the objectives of the discovery pro- gramme, as illustrated in Table 4. Clearly if the kinetic profile of compounds are not known then the ability to select compounds on a rational basis is lost.


Why are kinetics not investigated earlier in drug discovery?


Because kinetics generally are investigated only late in a programme after a lot of decisions have been made and triage carried out, the fact is that many compounds slightly less potent than those selected for progression, but with a much better kinetic profile, may already have been discarded.


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So, since having kinetic information would be really helpful to a discovery programme, why is it that kinetics based screening doesn’t already hap- pen on a regular basis?


A number of technologies are available to gener- ate kinetic information, and can be broken down into two broad types: those utilising a label such as a radiochemical or fluorophor, and label free tech- nologies which include surface plasmon resonance, biolayer interferometry and resonant acoustic pro- filing (for a more comprehensive review of available technologies see Comley13) Nonetheless, the fact that most laboratories use non kinetic measures to make an early selection decisions and make full kinetic measurements only on compounds that sur- vive this pre selection process14 is ample evidence that existing methodology does not currently enable a wider use of kinetic data. Some more accessible technologies, eg localised surface plas- mon resonance (LSPR) currently used to obtain affinities have, in the principle, the capability of generating kinetic data but this is not yet developed. Where laboratories generate kinetic data cur-


rently, it is likely that they will be using Biacore or a similar sensor-based system in their work, Biacore having by far the largest market share (29% in 2008 according to Comley, now likely to approach 50%). Until recently, Biacore enjoyed complete dominance of the kinetics-based label- free market due the virtual absence of credible alternatives and the Biacore name became synony- mous with both label-free and SPR. Yet despite this market dominance, and clear market interest in label-free methods, most label-free screening has remained a niche and specialist approach. Label- free competitors to Biacore came to market over


Drug Discovery World Summer 2011


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