Novel Androgen Receptor Antagonists for the Treatment of Prostate Cancer - Accounts in Drug Discovery Case Studies in Medicinal Chemistry - page 129

more mice and their development was discontinued. In the same study, BMS-
641988 showed clinical signs of decreased activity but no convulsions or death
over the entire dosing period. Findings of decreased activity were absent by the
end of the study and correlated with a 5-fold drop in maximal exposure with
repeat versus single dosing, likely due to CYP 3A enzyme induction since
hepatic transcript abundance for CYP 3A1 increased 10-fold and in vitro
reaction phenotyping studies with human P450s identified oxidation by CYP
3A4 as the principal metabolic route.
BMS-641988 exhibits higher AR binding a nity and significantly increased
potency as an antagonist of both wt and mutant AR transcriptional activity
compared with bicalutamide. 8 Although BMS-641988 showed potent antago-
nist activity in transactivation assays done with LNCaP cells transiently
transfected with the artificial reporter constructs, it also promoted the pro-
liferation of these cells. This T877A mutant AR agonist activity has been
observed with other potent anti-androgens, such as nilutamide and flutamide. 2
In a 14-day PD study in mature male rats, BMS-641988 provided a significant
reduction in the weights of ventral prostate and seminal vesicles as well as in the
percentage of nuclei stained positively for the proliferation marker Ki-67 in
prostate sections compared with the vehicle control. At daily oral doses of
10mg kg 1 and beyond, BMS-641988 demonstrated significant anti-tumor
activity in the CWR-22-BMSLD1 human xenograft mouse model. The tumors
were only marginally sensitive to 150mg kg 1 day 1 bicalutamide, which pro-
vided 3-fold higher steady-state exposures in mice than those obtained with its
clinical dose in humans. Animals receiving 90mg kg 1 day 1 of BMS-641988
exhibited tumor stasis during treatment (97% tumor growth inhibition) and a
3-fold delay in target tumor progression on cessation of treatment compared
with those receiving the highest dose of bicalutamide. Furthermore, BMS-
641988 decreased serum PSA levels, a surrogate marker for tumor burden in
humans, 18 up to 80% compared to the vehicle controls, whereas bicalutamide
caused less than 50% reduction in PSA. In addition, the e cacy of BMS-
641988 was demonstrated in the androgen-dependent LuCaP 23.1 xenografts
driven by wt AR.
The effectiveness of BMS-641988 as a second-line hormonal therapy was
assessed in CWR-22-BMSLD1 xenografts failing bicalutamide treatment. Mice
receiving daily bicalutamide at 150mg kg 1 showed a 3-fold increase in median
tumor size after 14 days of treatment. At this point, one group was switched to
treatment with BMS-641988 (90mg kg 1 ), and the remaining animals con-
tinued the treatment with 150mg kg 1 of bicalutamide. As shown in Figure 6.5,
animals switched to BMS-641988 showed minimal tumor growth, whereas
tumors from bicalutamide treated animals continued to grow progressively.
These data indicate that tumors that fail bicalutamide treatment retain their
sensitivity to BMS-641988.
BMS-641988 exhibited good oral bioavailability (64-95%) in mouse, rat,
dog, and cyno PK studies. Plasma half-life ranged from 2.4 h in mice to 21.8 h
in dogs. Based on low metabolic rates in human liver microsomes and hepa-
tocytes, as well as allometric scaling in comparison to other species, the human