Novel Androgen Receptor Antagonists for the Treatment of Prostate Cancer - Accounts in Drug Discovery Case Studies in Medicinal Chemistry - page 130

2000

1500

Vehicle
Bicalutamide, 150 mg/kg
BMS-641988, 90 mg/kg
Bicalutamide, 150 mg/kg
BMS-641988, 90 mg/kg

Therapy Switched to
BMS-641988

1000

500

0

15 25 35 45 55 65 75

Days post Implant

Figure 6.5 Anti-tumor activity of BMS-641988 in CWR-22-BMSLD1 xenografts
after failure to bicalutamide therapy. Reprinted with permission from
Cancer Res., 2009, 69, 6522.

clearance and plasma elimination half-life were predicted to be 0.75mL
min 1 kg 1 and 31 h, respectively. Given the significant discrepancy in the
observed half-life in mice and the predicted human half-life, BMS-641988 was
administered to CWR-22-BMSLD1 tumor-bearing mice via subcutaneous
mini-osmotic pumps to determine the sustained minimum exposure required
for ecacy. Greater than 50% tumor growth inhibition (TGI) was achieved
with a peak concentration of 0.53 mM, and an average steady-state con-
centration of 0.32 mM of BMS-641988. Analysis of the plasma samples from
this ecacy study revealed metabolism of BMS-641988 to BMS-949, with an
average steady-state concentration of about 2 mM BMS-949. Reaction pheno-
typing, using recombinant human isoforms and human liver microsomes,
determined that metabolism occurs via CYP 3A4 mediated oxidation of the C5
position of BMS-641988, followed by elimination of the sulfonamide to gen-
erate BMS-511, which is rapidly reduced by cytosolic reductase to BMS-949
(Figure 6.6). Both BMS-511 and BMS-949 are active metabolites of the
parent drug since they exhibit potent binding and functional antagonism to AR
(Table 6.1). In vivo characterization of BMS-511 could not be accomplished
since it was readily converted to BMS-949 in all preclinical species. The for-
mation of BMS-949 was of particular concern due to its ability to induce sei-
zures in rodents and dogs at high concentrations (4150 mM). However, a
comfortable safety margin was anticipated since only 2 mM steady-state con-
centrations of BMS-949 were observed in the minimum ecacious exposure
study with BMS-641988.
Due to the presence of a base-labile imide functionality, the parent form of
BMS-641988 is in a pH-dependent equilibrium with two regioisomers of the