Chemistry Reference
In-Depth Information
Me
Me
O
O
H
H
6
CYP 3A4
6
O
N
CN
O
N
CN
1
1
5
HO
5
H
H
CF
3
CF
3
O
O
Me
Me
6
BMS-949
Figure 6.3
Oxidative metabolism of 6.
activity at 10 mM. In a two-week exploratory toxicity study in male rats, BMS-
949 was well tolerated at daily oral doses of 2.5 and 25mg kg
1
with dose-
proportional exposure and no adverse non-mechanism based pharmacological
changes. However, convulsions were observed at the highest dose tested of
250mg kg
1
at approximately T
max
following three days of dosing. In a 10-day
exploratory toxicity study in male dogs, convulsions occurred following five to
six days of daily oral dosing at 25 and 50mg kg
1
. In one-month rat and dog
studies with maximum doses selected to be below those producing convulsions
in the prior two-week rat and 10-day dog studies, pharmacology (prostate
atrophy) without toxicity was observed. These studies established a no adverse
effect level (NOAEL) at systemic exposures that were 2- to 4-fold (rat and dog,
respectively) of the ecacious exposure required in CWR-22-BMSLD1 tumor
xenograft studies. Convulsions can be life threatening both directly (e.g., by
interrupting respiration) and indirectly (e.g., by accidents following loss of
consciousness while driving a car or while walking on stairs). Because of the
serious consequences of convulsions, the lack of predictive symptoms preceding
their onset, and the often steep exposure-convulsion relationship, regulatory
guidance on the starting human dose is to increase the safety margins for
human testing when convulsion is an identified hazard.
15
In light of the low
safety multiples for the observed CNS effects and the expected chronic treat-
ment regimen for an AR antagonist, human testing of BMS-949 was not
pursued.
Following discontinuation of the development of BMS-949, a series of stu-
dies were designed to investigate the underlying cause of the convulsions and to
improve the screening strategy for the identification of new AR antagonists.
These studies attempted to answer the following. (a) Were convulsions specific
to the structural class under investigation? (b) Were the convulsions an on-
target effect of AR modulation? (c) Was there potential explanatory off-target
pharmacology for the convulsions? (d) Were the convulsions due to seizure in
the central nervous system (CNS) or were they due to a peripheral effect, such
as in the muscle or at the neuromuscular junction? The outcome of these studies
has been described in detail elsewhere.
16
In brief, deaths and/or convulsions
were observed in male mice following oral administration of a structurally
diverse set of AR antagonists, including the clinical anti-androgens nilutamide
and flutamide. Convulsions were also observed in studies with AR knockout
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