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11. Gao, W.; Kearbey, J. D.; Nair, V. A.; Chung, K.; Parlow,
A. F.; Miller, D. D.; Dalton, J. T. Endocrinology 2004,
145, 5420.
12. Sun, C.-Q.; Robl, J. A.; Wang, T. C.; Huang, Y.; Driscoll,
J. E.; Lupisella, J. A.; Beehler, B. C.; Golla, R.; Sleph, P.
G.; Seethala, R.; Fura, A.; Krystek, S. R., Jr.; An, Y.;
Malley, M.; Sack, J. S.; Salvati, M. E.; Grover, G. J.;
Ostrowski, J.; Hamann, L. G. J. Med. Chem. 2006, 49,
7596.
13. Ostrowski, J.; Driscoll, J. E.; Lupisella, J. A.; Manfredi,
M. C.; Beehler, B. C.; Bi, Y.; Sun, C.-Q.; Seethala, R.;
Golla, R.; Sleph, P. G.; Fura, A.; Narasimhan, N.;
Krystek, S. R., Jr.; An, Y.; Kish, K.; Sack, J. S.;
Bonacorsi, S. J.; Cao, K.; Mookhtiar, K. A.; Grover, G.
J.; Hamann, L. G. Endocrinology 2007, 148, 4.
10 mg/kg dose of 3a restored levator ani weights to those
of TP treated animals, both groups achieving approxi-
mately 70% that of intact, vehicle-treated, sham-oper-
ated controls. However, the effect on prostate at this
dose was substantially weaker than that for TP, giving
only a 10% response relative to intact controls compared
with 70% induced by TP. This observed muscle selectiv-
ity for 3a is consistent with the desired pharmacological
profile of a SARM which might be suitable for treat-
ment of sarcopenia.
High affinity androgen agonists were obtained upon
substitution of the bicyclic imide moiety of 2 with a sul-
famide group, exemplified by compound 3a. Further
modification of 3a to invert the hydroxyl group stereo-
chemistry, reduce the bridging carbonyl or hydrolyze
the ring resulted in dramatic loss of biological activity.
In this system, hydroxyl substitution at C4 is preferred
over C5, and the 4-(R) diastereomers are more active
than the corresponding 4-(S)-isomers. Structural
changes to 3a caused substantial decreases in functional
activity in cell-based assays while in many cases retain-
ing comparable to moderately reduced binding affinity.
In most cases, switching from a carbonyl to an isosteric
sulfonyl moiety resulted in compounds with weak par-
tial agonist profiles. In general, the acyl sulfamide core
appeared less tolerant of significant structural modifica-
tions than the corresponding hydantoin compounds.4,18
Nonetheless, investigation of the acyl sulfamide scaffold
yielded in vivo active, muscle-selective AR agonists, and
this template provides a potential alternative to the
hydantoin SARMs previously reported.
14. Ducry, L.; Reinelt, S.; Seiler, P.; Diederich, F. Helv. Chim.
Acta 1999, 82, 2432.
15. A typical procedure for preparation of SARM 3a follows: to
a solution of 5 (100 mg, 0.60 mmol) in 3 mL of CH2Cl2 at rt
was added chlorosulfonic acid (44 lL, 0.66 mmol) followed
by PCl5 (125 mg, 0.60 mmol) and the suspension refluxed
for 30 min. The suspension was cooled to rt and added
dropwise to a solution of 0.25 mL of NEt3 in 1 mL of
CH2Cl2 cooled to 0 ꢁC. Diisopropylethylamine (0.21 mL,
1.20 mmol) was added followed by 8a (120 mg, 0.660 mmol)
and the solution stirred at 0 ꢁC for 30 min. The reaction
mixture was washed with brine, dried (MgSO4), filtered, and
concentrated. The residue was purified by flash chromatog-
raphy (silica gel, CH2Cl2/CH3OH, 98:2, 95:5, and 90:10) to
afford 6a. A solution of 6a (109 mg, 0.29 mmol) in 15 mL of
1.6 N NaOH was stirred at rt for 1 h. The reaction mixture
was acidified to pH 2 with 10% HCl and extracted with
EtOAc. The organic layer was dried (MgSO4), filtered, and
concentrated to afford 6b. To a suspension of 6b (82 mg,
0.23 mmol) in 5 mL of CH3CN at rt was added DCC
(47 mg, 0.23 mmol) followed by p-nitrophenol (63 mg,
0.46 mmol). The suspension was refluxed for 1 h, cooled
to rt, and filtered. The filtrate was concentrated and the
residue dissolved in EtOAc, washed with water and brine,
dried (MgSO4), filtered, and concentrated. The residue was
purified by flash chromatography (silica gel, EtOAc/hex-
anes, 50:50 and 75:25) to afford 3a (61 mg). 1H NMR
(400 MHz, CD3OD) d 2.21–2.23 (m, 2H), 2.37, 2.39 (s, 3H),
3.61–3.64 (m, 1H), 3.97–4.04 (m, 1H), 4.66, 4.68 (s, 1H), 4.79
(d, J = 3.85 Hz, 1H), 7.45, 7.55 (d, J = 8.25 Hz, 1H), 7.83 (d,
J = 8.25 Hz, 1H); HPLC:Phenomenex C18 4.6 · 50 mm,
4 min gradient, 10% MeOH/90% H2O/0.1% TFA to 90%
MeOH/10% H2O/0.1% TFA; 1 min hold, 4 mL/min UV
detection at 220 nm, 2.65 min retention time; MS (ES): m/z
340 [MÀH]À.
References and notes
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17. Rat pharmacokinetics (5 mg/kg iv, 10 mg/kg po):
Cmax = 8.4 lM,
F = 53%.
CL = 12.8 mL/min/kg,
T1/2 = 0.9 h,
18. Li, J. J.; Sutton, J. C.; Nirschl, A.; Zou, Y.; Wang, H.; Sun,
C.-Q.; Pi, Z.; Krystek, S. R., Jr.; Seethala, R.; Golla, R.;
Sleph, P. G.; Beehler, B. C.; Grover, G. J.; Fura, A.; Vyas, V.
P.; Li, C. Y.; Gougoutas, J. Z.; Galella, M. A.; Ostrowski, J.;
Hamann, L. G. J. Med. Chem. 2007, 50, 3015.
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