Novel Androgen Receptor Antagonists for the Treatment of Prostate Cancer - Accounts in Drug Discovery Case Studies in Medicinal Chemistry - page 128

Me

Me

O O

H

H

O

O N CN N CN

X

HO

3'

H

H

CF 3

O I O

Me

Me

7 ,X=NHCOEt
8 ,X=NHSO 2 Ph
BMS-641988, X = NHSO 2 Et

BMS-305

Figure 6.4 Lead compounds in the oxabicyclo[2.2.1] imide series.

toxicity studies. A less than dose-proportional increase in exposure limited
maximum achievable systemic exposures in both species. Unfortunately,
alterations in the levels of thyroid hormones T 3 and T 4 , as well as significant
quantities of the de-iodinated metabolite of BMS-305 in plasma, were detected
following two weeks of dosing in rats and following 10 days of dosing in dogs.
Subsequent studies demonstrated that BMS-305 was a substrate of 5 0 -deiodi-
nase, leading to interference with thyroid hormone homeostasis. Although
further development of BMS-305 was terminated, these studies demonstrated
that it was possible to identify oxabicyclo[2.2.1] imide-based potent AR

antagonists that lacked significant CNS liabilities.

6.4 Clinical Leads

6.4.1 Discovery of BMS-641988
At this stage, attention was focused on optimizing functional groups on the C5-
C6 bridge of the bicyclic scaffold. Modeling studies suggested that the bridging
oxygen atom can forge a hydrogen bonding interaction with N705 in the AR
LBD. Endo substitution at C5 or C6 of the core would result in a steric clash
and a possible displacement of helix-12, similar to the proposed antagonist
conformation of bicalutamide. 2 A variety of functional groups, including
amides, carbamates, sulfamides, ureas, and sulfonamides, were tolerated at the
C5 or C6 positions. 17 Three compounds with highly desirable in vitro potency
profiles (Table 6.1) are shown in Figure 6.4. With daily oral administration of a
10mg kg 1 dose, these compounds produced PD effects similar to castration in
the three-day IRPW assay.
Exploratory studies in mice with BMS-949 suggested that convulsions can
occur at lower doses with repeat versus single-dose regimen. This finding may
be due to a combination of drug accumulation, poor tolerability, or time-
dependent increases in seizure sensitivity. Therefore, the selection process was
modified to include a five-day mouse behavioral study for lead compounds that
passed seizure screening with a single high dose. In the five-day mouse toxicity
study at 450mg kg 1 day 1 , amide 7 and sulfonamide 8 were lethal to one or