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Me
Me
O
H
H
CO
2
H
O
HN
CN
O
HN
CN
+
CO
2
H
EtO
2
SHN
EtO
2
SHN
H
H
CF
3
CF
3
O
Me
Me
Me
O
H
9
10
O
N
CN
5
EtO
2
SHN
H
CF
3
Me
Me
O
O
Me
O
H
H
CYP 3A4
reductase
O
N
CN
O
N
CN
BMS-641988
HO
O
H
H
CF
3
CF
3
O
O
Me
Me
BMS-949
BMS-511
Figure 6.6
BMS-641988: stability and metabolism.
open imide form (Figure 6.6). In all animals investigated, BMS-641988 was the
favored species, with the open imide isomers being generated in concentrations
of 8-15% of the parent. While this equilibrium did not raise any additional
safety or ecacy concerns, it necessitated additional analytical steps to monitor
levels of the parent drug and its metabolites in subsequent studies.
6.4.2 Preclinical Safety Profile of BMS-641988
In a one-month toxicity study in rats, pharmacologic effects were observed in
the prostate at all doses and there were no behavioral changes at any dose.
Exposures decreased by 50% at the high dose of 250mg kg
1
day
1
from day 1
to day 29, while liver weights increased by 50%. Exposures of BMS-641988 at
this dose were approximately 50-fold higher than the minimum exposure
required for ecacy in xenograft models. BMS-949 was the most abundant
metabolite in circulation, but only at low exposure levels, thus providing a
comfortable margin with respect to the CNS threshold.
In a one-month toxicity study in dogs, pharmacologic effects were observed
in the prostate at all doses. Clinical signs of toxicity observed at and above the
25mg kg
1
day
1
dose included ataxia, decreased activity, and loss of righting
reflex, but not convulsions. At the lowest dose, where no clinical signs of
toxicity were observed, plasma concentrations of BMS-641988 were approxi-
mately 20-fold of the ecacious exposure in tumor models. In contrast to
BMS-949, which is highly brain penetrant, whole brain concentrations of BMS-
641988 did not exceed 10% of plasma values in dogs at 24 h post-dose. Very
low levels of BMS-949 were detected in the dog toxicity studies, resulting in a
high safety multiple (4100) for seizure effects.
Binding data for cardiac ion channels and in vitro electrophysiology studies
suggested low potential for cardiovascular liabilities with BMS-641988. How-
ever, BMS-641988 produced dose- and exposure-related reversible QT pro-
longation in telemetrized dogs with a no-effect concentration of 5-fold the
projected maximal exposure required for ecacy. BMS-641988-dependent QT
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