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24-h delay. The data from this and the auditory sensory gating in vivo models
provided important evidence that in rats, PHA-543613 positively influenced
sensory gating and memory, both of which are believed to be disrupted in
patients with schizophrenia.
Of the 6,5-fused heterocyclic amides of 3-aminoquinuclidine evaluated,
PHA-543613 proved to be a potent, high-anity agonist of the a7 nAChR. The
excellent in vitro PK profile of this compound was matched by rapid brain
penetration, high oral bioavailability, and a favorable hERG profile. Fur-
thermore, PHA-543613 demonstrated e
cacy in two in vivo models of disease
relevance. The data generated with this compound provide additional support
for the hypothesis that a7 nAChR agonists represent a potential pharma-
cotherapy for the treatment of cognitive deficits in schizophrenia. The favor-
able in vitro and in vivo ecacy and safety profile of PHA-543613 made it an
attractive candidate for clinical study. Regulatory toxicology studies before
human studies uncovered no liabilities that would preclude further develop-
ment of the compound. The main safety findings that required the development
of a backup candidate were CNS signs in both rats and dogs and slight pro-
longation of the QTc interval in dogs at levels projected to be significantly
above therapeutically relevant exposures. The CNS signs included seizures
associated with maximal plasma concentrations 410 mM.
15.4 The Search for a Backup
15.4.1 Defining a Backup Strategy for Improving the Safety
Profile
While the first-generation compound PHA-543613 was undergoing further
profiling in preparation for clinical studies, the team felt it was critical to pursue
a backup program for this important target. The program objective was to
identify one or more novel, potent, and orally bioavailable a7 nAChR agonists
with in vitro and in vivo profiles equal to or better than those of PHA-543613.
The strategy also called for a backup compound that differentiated itself from
PHA-543613, making it less susceptible to any potential failures seen in the
PHA-543613 trials. Without human clinical data to guide the development of
backup compounds, we focused on further improving the safety margins of
PHA-543613 against two endpoints: QTc prolongation and convulsions in dog
models. Although PHA-543613 showed adequate safety margins against these
findings, QTc prolongation had the potential to be dose limiting in the clinic,
and thus the team sought opportunities for further improvement. Because this
medication would be administered chronically as an adjunctive therapy, it was
believed that a compound with at least a threefold improvement in each of the
safety areas mentioned above represented an opportunity for differentiation
from PHA-543613.
The chemical strategy for identifying a backup compound focused on the
quinuclidine aryl amide template (Figure 15.9). When PHA-543613 was
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