Novel Androgen Receptor Antagonists for the Treatment of Prostate Cancer - Accounts in Drug Discovery Case Studies in Medicinal Chemistry - page 133

Me

H H

OMe

O

N CN N CN

S

O H F

O

H

CF 3 CF 3

O O

MeHN

Me

O

11 12

Figure 6.7 Lead compounds in the lactam and sultam series.

Significant differences in SAR between the imide and lactam series suggested
that the imide carbonyls may be important to enhance the AR antagonist profile
of these compounds. Extensive medicinal chemistry efforts to improve the overall
profile of these related series included detailed functional group manipulation at
each position of the tricyclic core. One such avenue of exploration to modify one
of the quaternary methyl groups of the tricyclic lactam yielded an unanticipated
result. Attempted reduction of a hydroxyethyl-substituted tricyclic imide 13 led
to the novel tetracyclic compound 15, instead of a corresponding tricyclic lactam
14 (Figure 6.8). Compound 15 showed high level of binding and potent antag-
onism to AR (Table 6.2). In spite of the presence of an ''aminal-like'' func-
tionality in these molecules, pH-dependent solution-state stability studies
established that the tetracyclic scaffold was stable over a broad pH range (2.0-
7.4) for two weeks at 50 1C. The observed stability may be related to the sig-
nificantly reduced basicity of the aniline nitrogen atom. In addition, the con-
strained pyran ring may provide added chemical stability to these compounds.
SAR studies suggested that a variety of functional groups (e.g., alcohol,
carbamate, sulfonamide, etc.) were tolerated on the C2-C3 two-carbon bridge
of the tetracyclic ring system. As shown in Table 6.2, compound 16 exhibited an
excellent in vitro profile and provided castration level PD effects at a low daily
dose of 3mg kg 1 in the IRPW assay (Figure 6.9). However, it failed to elicit a
significant level of ecacy in the CWR-22-BMSLD1 tumor xenograft model,
even at a daily dose of 150mg kg 1 . Analysis of the plasma samples from the
tumor study suggested that the observed lack of activity may be related to the
inability of the compound to provide sustained AR antagonism for the dura-
tion of time between doses. Plasma exposures of the compound were excellent
(425 mM) for the first 8 hours after dosing, but the trough exposures (0.06 mM,
87% protein binding) were not sucient to completely antagonize the andro-
gen receptor, given the compound's antagonist IC 50 value of 226 nM. This
result highlighted the need to improve PK properties in this lead series. Bio-
transformation studies confirmed that the endo-carbamate moiety was the
primary site of metabolism for 16. N-Dealkylation of the carbamate moiety via
oxidation at the carbon bearing the carbamate nitrogen led to the formation of
inactive ketone and alcohol metabolites. Importantly, these studies indicated
that the tetracyclic framework offered a satisfactory level of metabolic stability
under physiologic conditions.