Letters
Journal of Medicinal Chemistry, 2007, Vol. 50, No. 26 6445
In salt-loaded, uninephrectomized Sprague–Dawley rats, 14
was more potent than 1 on a dose basis.8 After 14 days (po,
qd), a 3 mpk dose of 14 showed equivalent blood pressure
lowering to 1 at 30 mpk, as shown in Figure 2. Interestingly,
indole 3 was not active at 3 mpk (data not shown). By adding
the ortho-fluoro in 14, the result is a very potent and efficacious
compound. Clearly, 14 compares favorably to 1 regarding in
vivo potency.
Analog 14 is a potent, selective, orally efficacious antagonist
of the mineralocorticoid receptor. The analog based on the indole
scaffold is more potent than the marketed drug 1 in a rat model
for hypertension and offers a better in vitro selectivity profile
than the standard spironolactone. Clinical side effects surround-
ing the current therapies in the steroidal class of molecules make
a small molecule inhibitor a valued strategy for treating
hypertension and congestive heart failure. The optimal indole
14 and related analogs may offer clinicians a valuable tool in
the fight against these critical disease states.
Figure 2. Reduction in aldosterone-induced (0.75 ug/hr, s.c.) hyperten-
sion by mineralocorticoid antagonists (1–100 mg/kg/day, po × 14 days).
7-methanesulfonamide indole 5 under acidic conditions, usually
trifluoroacetic acid, to give the 3-alkylated indole as a racemic
mixture. Chiral separation afforded the individual enantiomers,
giving 3 in 95% enantiomeric excess.9,10
Acknowledgment. The authors would like to acknowledge
Keith Stayrook for hGR binding data and Harold Osborne for
hER binding data. The authors would also like to thank Nathan
Mantlo for his helpful discussion and the Analytical Technolo-
gies group for related pchem.
The racemic mixture of 14 proved to be a very challenging
chiral separation on scale. However, by modifying the synthetic
route and subjecting the racemic amino indole (12 and 13) to
an optimized chiral resolution, a significant advancement in
separation was achieved.9,10 This was ultimately a critical step
in the prosecution of this molecule. Again, starting with the
commercially available 7-nitro indole, 4, and cyclopropyl phenyl
ketone, 8, analog 14 was prepared in a five-step synthesis, as
shown in Scheme 2.7 In the manner of Scheme 1, the
difluorophenyl geminal dialkyl carbinol 9 was condensed with
the protected amino indole 10 under acidic conditions to give
the 3-alkylated indole 11. Deprotection followed by chiral
resolution of the resultant aniline offered optimal separation,
giving the pure S-enantiomer 12. Finally, mesylation and
recrystallization gave the final compound 14. The absolute
stereochemistry of 3 was unambiguously determined through
single crystal X-ray analysis to be the S-enantiomer, as shown
in Figure 1. Correlative studies utilizing chiral HPLC and optical
rotation identified 14 as also having the S-absolute configuration.
The indole series was found to be potent, selective MR
antagonists, as exhibited by 3 and 14. Human MR (hMR) and
selectivity binding, as well as functional activity, proceeded as
described in the literature.6,7 Members of this class of com-
pounds showed greater than 10-fold selectivity against related
receptors in the steroidal class based on binding presented in
Table 1.
In benchmarking against reference compounds, the selectivity
profile for 14 is similar and, in some cases, exceeds that of 1.
Most importantly, the AR and PR selectivity window is well
above that of 1 and spironolactone, offering a distinct advantage.
In the indole examples, the S-enantiomer was about 3-fold more
potent in either the binding or the functional assays. Simply
going from a para-fluoro to an ortho,para-difluoro phenyl, an
increase in binding affinity was realized that persists throughout
the flowscheme. Analog 14 is a high affinity (MR Ki ) 0.494
( 0.23 nM), functional antagonist (Kb ) 19 ( 12.8 nM) with
reasonable in vivo efficacy and potency. Most importantly, 14
showed greater binding affinity than 1, a trend mirrored in the
functional and in vivo setting as well.
Supporting Information Available: Experimental procedures
and characterization data for 14 and other indole analogs and a
detailed description of in vivo assays. This material is available
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