Chemistry Reference
In-Depth Information
steady-state total plasma trough (C
ss,min
) for the low dose and never
o
94% at
the middle or high dose (Figure 15.15).
These data have important implications from an ecacy perspective when
considering the ability of neuronal ion channels to desensitize with excess
activation. If high degrees of RO coupled with intrinsic agonist activity would
lead to receptor desensitization, then ecacy, which in this case is agonist
activity associated with improved cognition, could be lost at unnecessarily
elevated ROs. This consideration is critical for cognition-enhancing targets that
usually demonstrate hormetic dose-response curves.
71,72
Thus it is crucial to
understand the RO range required for a desired effect from a ligand with a
specific intrinsic agonism so that the optimal dose may be tested clinically. In
the case of PHA-543613, the clinical doses evaluated in the MD study suggest
from a RO standpoint that lower doses (i.e.,
r
6mgbid) may have been most
optimal for a cognition trial in patients with schizophrenia.
An additional influence for ecacy other than dose is dosing interval, which
affects C
ss,max
and the steady-state total plasma trough (C
ss,min
) concentrations
and their temporal relationships. The implications for dosing interval are
related to the amount of time required for the receptor to ''reset'' to its active
form after a desensitizing exposure. If, for example, a desensitized receptor
requires that agonist concentration fall below a specific threshold for a certain
period of time to revert to its fully functional form, then the dosing interval of a
chronic dosing regimen would be critical in ensuring optimized ligand-receptor
interactions for testing agonist-mediated ecacy.
One last consideration building on these concepts is that if a specific RO
o
90% was required for ecacy and did not prompt receptor desensitization,
then targeting such an RO would require lower ECF concentrations, which
would directly translate to lower plasma concentrations. This detail is impor-
tant in light of the deleterious cardiovascular events observed clinically with
PHA-543613. Lower doses targeting lower ROs would require lower systemic
concentrations, which might expand therapeutic indices for observed cardio-
vascular adverse events specifically and decrease total body load to compound
generally. Taken together, these human RO estimations suggest that lower
doses of PHA-543163 could have been evaluated clinically for optimizing
ecacy (i.e., not leading to receptor desensitization and hence overshooting
ecacy) while expanding therapeutic indices for cardiovascular adverse events.
Studies exploring these concepts, particularly dosing regimen, could be pre-
pared more fully before further clinical evaluation of other a7 nAChR agonists
to optimize clinical outcomes.
15.8 Conclusion
Our studies of a7 nAChR agonists clearly show the benefit of developing a deep
and well-defined screening strategy. Starting with the right HTS assay to
identify quality hits and pursuing only those that demonstrate desirable
properties are keys for success. The application of parallel medicinal chemistry
Search WWH ::
Custom Search