Chemistry Reference
In-Depth Information
During Phase I single ascending dose (SAD) and multiple ascending dose
(MAD) safety, tolerability, and PK studies, PHA-543613 demonstrated linear
pharmacokinetics and a suitable half-life in human (
9-12 h).
47
In the Cog-
State cognition testing battery,
54
patients showed a modest improvement in
cognitive function at the low dose.
55
Similar Phase I SAD and MAD safety,
tolerability, and PK studies were completed with PHA-568487.
During dosing of the first group of subjects in the PHA-568487 MAD study,
two subjects experienced episodes of nonsustained ventricular tachycardia
(NSVT) and one subject exhibited an increased frequency of premature ven-
tricular contraction. During the PHA-543613 studies, one subject in the SAD
study experienced an episode of NSVT, and one subject in the MAD study
experienced NSVT. A low-frequency of cardiovascular arrhythmia was also
observed during this study, and there was no evidence of QTc prolongation or
other electrocardiographic interval changes associated with the episodes of
arrhythmia. An analysis of the SAD and MAD studies (N
¼
68 for PHA-
543613; N
¼
25 for placebo) found no evidence of a direct relationship between
the drug concentration and cardiac arrhythmia.
Recently, however, the clinical development of both PHA-543613 and PHA-
568487 has been discontinued owing to a low incidence (5%) of asymptomatic
NSVT and premature ventricular contraction in healthy volunteers.
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It is
unclear whether this side effect is related to the target or the class of com-
pounds, and we are pursuing additional research to elucidate its origin. A full
understanding of the potential safety concerns should emerge with the data
from clinical trials of partial and full agonists of the a7 nAChR.
B
15.6 Attempting to Overcome Clinical Toxicology
Findings: Merging Novel Templates to Develop
Additional Drug Candidates
Despite consultation with an external cardiology expert, we were unable to
determine whether the cardiac side effects seen in Phase I studies of PHA-
543613 and PHA-568487 were related to a7 nAChR agonism or to molecular
structure. Because both compounds belong to the quinuclidine amide structural
class, we decided that the best path forward would be to advance a compound
from a novel, non-quinuclidine-containing chemotype. Fortunately the inte-
gration of two organizations, Pfizer and Pharmacia, afforded a unique
opportunity to pursue a program focused on the 1,4-diazabicyclo[3.2.2]no-
nane-4-azabenzoxazole series of a7 nAChR agonists. This series had been
discovered by the legacy Pfizer team, and could now be profiled in the deep in
vivo biology assays developed by the Pharmacia team.
In previous work, we selected PHA-543613 as the target profile for a backup
compound for several reasons: (1) PHA-543613 was characterized as a potent,
subtype-selective, a7 nAChR full agonist with no a7 nAChR positive allosteric
modulator activity; (2) the ADME profile of this compound in humans was
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