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Me
O
O
O
H
H
H
7
O
N
NO
2
O
N
CN
O
N
CN
H
H
4
H
O
O
CF
3
O
CF
3
Me
4
6
5
Figure 6.2
Hit-to-lead progress in the oxabicyclo[2.2.1] imide series.
oxabicyclic ring system. Appending methyl groups from the two bridgehead
positions would be expected to result in positive lipophilic interactions with
each of the methionine residues, thus generating improved binding anity to
the AR. Indeed, the dimethyl analog 6 showed almost a 100-fold improvement
in binding anity and a commensurate increase in antagonist activity as
compared to 5.
Upon daily oral administration of just a 1mg kg
1
dose, 6 exhibited excellent
PD effects in the immature rat prostate weight (IRPW) assay. However, the
extent of the observed in vivo potency of this compound did not correlate with
the very low plasma exposures of this compound (below the IC
50
in the
transactivation assay) that were achieved in this study. Since this result was
suggestive of the presence of an active metabolite, a rapid bioassay-guided
method was designed to generate and detect potential active metabolites.
13
This
method confirmed the presence of a single oxidative metabolite with potent AR
antagonist activity. Based on the reported metabolite profile for a similar
oxabicycle,
14
hydroxylation at either the C5 or C6 position of 6 was hypo-
thesized. Concurrent efforts in chemical synthesis and LC-NMR analysis
confirmed that BMS-949 (Figure 6.3) was the active metabolite of 6. Chiral
HPLC analysis showed that the oxidative metabolism was highly enantiose-
lective (499% enantiomeric excess), resulting in the exclusive formation of the
exo-alcohol. Subsequently, BMS-949 was shown to be the major metabolite
formed by CYP 3A4 mediated oxidation of 6 in both rodent and human liver
microsomes (Figure 6.3).
BMS-949 demonstrated potent binding to, and antagonism of, the AR
(Table 6.1). Importantly, it exhibited excellent oral bioavailability (485%) and
long half-life (10 h in mice to 28 h in dogs) in animals. At a low oral dose of
1mgkg
1
, BMS-949 provided PD effects comparable to castration control in
the IRPW assay. In the CWR-22-BMSLD1 human tumor xenograft model,
BMS-949 (30 and 90mg kg
1
, po, qd) showed superior ecacy compared to the
highest achievable dose of bicalutamide (150mg kg
1
day
1
).
6.3.2 Preclinical Safety Evaluation of BMS-949
In the in vitro competitive binding safety pharmacology assays of 25 off-target
transporters, ion channels, and receptors, BMS-949 did not exhibit significant
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