Drug Discovery
in a steeper dose response curve but at the price of a narrowed therapeutic interval11. In examples such as this, because the need to achieve critical concentration in a short time is the crucial factor in determining efficacy, on-rate is a much better pre- dictor of efficacy than Ki.
How could we apply on and off-rate properties to enable better drug discovery? In vitro screening
Understanding of kinetics at early stages of Drug Discovery, even at the screening phase, ie before many compounds have been rejected, gives access to more diverse chemical space, more scope for intellectual property (IP) and patents, and better defined biology. Receptor selectivity can be driven by off-rate and not necessarily affinity and affinity and off-rate SAR may diverge with large differ- ences in dissociation rates within a chemical series being not uncommon. In addition to kinetics at the primary target, this principle can apply equally to off target effects in respect of selectivity and safety issues. Where SAR diverges it may be possible to achieve a greatly improved safety profile by select- ing compounds from the series based on their on/off-rates at proteins of concern.
In vivo screening Generally, better in vivo profiles are apparent with slow off compounds, less variation in receptor occupancy between peak and trough plasma con- centrations leading to a smoother efficacy curve. Slow off-rates also are more likely to lead to a once-a-day dose projection, which can be an important differentiator.
Understanding on and off-rates may help us rec- oncile currently puzzling mismatches in efficacy, selectivity or safety between humans and animal
laboratory species. If on/off-rates vary in human versus animal receptors, an expected margin of safety observed in one species could disappear due to different kinetic profiles in the human at the rel- evant receptors – or vice versa: a compound reject- ed due to poor margin of safety or selectivity in an animal species could be, in fact, adequately selec- tive for the desired over the unwanted effects in human. Such variations would be particularly important where efficacy and safety studies are conducted in different species.
Is a fast Koff of use? It is possible to envisage that iv dosage forms of a drug with fast off-rate would enable a fast wash out of drug – short acting anaes- thetic perhaps, or other use where tight control on the duration of effect would be valuable.
Manipulation of kinetic profiles An understanding of kinetics, at an early stage in a lead seeking programme, could give real assistance by knowing in which areas to focus where a com- pound falls short of required effectiveness. Is there such a thing as a ‘good kinetic profile’? Geitmann12 describes a study of HIV-1 protease inhibitors where structural manipulation was able to produce a range of on and off-rates such that the compound properties could be used to map inhibitors into clusters that related their properties to their poten- tial utility as drugs. Note here the different proper- ties of association and dissociation rates. Association rates are related to the structure of the compound and to the dosage, while dissociation rates are solely dependent on the molecular struc- ture. However, receptor kinetics are of even more use if we view them in conjunction with the phar- macokinetic properties of the compounds. Where in vivo performance is sub-optimal, by considering all of this data we would understand the reason for the poor efficacy and how this might be improved.
Table 3: Selectivity conferred by differing kinetics at receptor subtypes COMPOUND
RECEPTORS Tiotropium NPY/PYY ICI 137,798 SCH 527123
M3 versus M2, M1 muscarinic receptor
NPY1 versus NPY2
Beta 1 versus Beta 2 adrenoceptor
CXCR1 versus CXCR2
DATA
M3 off-rate much slower than M2 or M1 off-rate
Y1 off-rate = 1 hour Y2> 24 hours
Beta 2 off-rate 30 min Beta 1 > 6 hours
CXCR1 off-rate 10 min CXCR2 20 hours
Drug Discovery World Summer 2011
LITERATURE REFERENCE
Disse, 19999 Dautzenberg, 200518 Keith, 198919 Gonsiorek, 200720
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