Novel Androgen Receptor Antagonists for the Treatment of Prostate Cancer - Accounts in Drug Discovery Case Studies in Medicinal Chemistry - page 122

OH

Me O

Me OH

Me

O

17 N

H
N

HO

S

Me H D

Me

O

O

A H H

F CN

NO 2

O

CF 3

CF 3

H

DHT

bicalutamide

2-hydroxyflutamide

O

O O

7 H

H H

6

4' N

N N NO 2

3

N

5 2

3'

4 H H

CF 3

O CF 3 O O

1 2 3

Figure 6.1 DHT and initial AR antagonist leads.

of (R)-bicalutamide at the clinically ecacious dose of bicalutamide was
21.6mg L 1 (50 mM). 6 Therefore, the desired development candidate needed to
exhibit a robust pharmacokinetic (PK) profile upon oral administration, and be
well tolerated at adequate multiples of the ecacious concentration.
Structure-based tools for the rational design of novel AR antagonists were
not available at the start of the program because co-crystal structures of ligands
with the AR LBD had not been solved. In 2001, BMS reported the first crystal
structures of the LBD of the AR, and its T877A mutant, complexed with the
natural agonist DHT. 7a In these structures, ring A of DHT (Figure 6.1) is
engaged in hydrogen bond interactions with the side chains of R752 and Q711.
In addition, the hydroxyl group of DHT is within hydrogen bonding distance
of N705 and T877. In the mutant LBD, replacement of T877 with alanine
creates additional space near the D ring of DHT to accommodate a larger
substituent near position 17. This provided a rationale for the promiscuous
ability of the T877A mutant AR present in the LNCaP prostate cells to bind
additional hormones, such as progesterone, in the agonist conformation. The
X-ray crystal structure of (R)-bicalutamide bound in an agonist conformation
to the W741L mutant AR LBD has been reported. 7b These crystal structures
provided molecular rationale for the design of novel AR pan-antagonists.

6.2.2 Biological Assays
The general paradigm employed in this program and the primary assay
information have been recently published. 8 A radioligand AR-competitive
binding assay was performed using [ 3 H]-DHT and human breast adenocarci-
noma MDA-MB-453 cells expressing endogenous wt AR. The effect of com-
pounds on the transcriptional activity of AR was determined in cell lines