3348
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Figure 3. The X-ray crystal structure of 3h-II hydrochloride indicating
an aR-configuration of the higher affinity atropisomer.
7. Struthers, R. S.; Xie, Q.; Sullivan, S. K.; Reinhart, G. J.;
Kohout, T. A.; Zhu, Y. F.; Chen, C.; Liu, X. J.; Ling, N.;
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2006, 91, 3903.
interaction with the receptor. The X-ray crystal struc-
ture of 3h-II as a hydrochloride salt was obtained
(Fig. 3) and its absolute stereochemistry was determined
to be aR-configured.24
9. Oki, M. Top. Stereochem. 1983, 12, 1.
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E.; Gross, T. D.; Guo, Z.; Zhu, Y. F.; Struthers, R. S.;
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12. For a recent example, see: Guile, S. D.; Bantick, J. R.;
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(b) Friary, R. J.; Spangler, M.; Osterman, R.; Schulman,
L.; Scherdt, J. H. Chirality 1996, 8, 364.
14. Guo, Z.; Chen, Y.; Huang, C. Q.; Gross, T. D.; Pontillo,
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Bioorg. Med. Chem. Lett. 2005, 15, 2519.
15. Tucci, F. C.; Zhu, Y. F.; Guo, Z.; Gross, T. D.; Connors,
P. J., Jr.; Gao, Y.; Rowbottom, M. W.; Struthers, R. S.;
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16. The lack of an additional phenyl ring presented in 2a
was also preferred for proton and carbon NMR studies
of 3a.
17. Guo, Z.; Zhu, Y.-F.; Gross, T. D.; Tucci, F. C.; Gao, Y.;
Moorjani, M.; Connors, P. J., Jr.; Rowbottom, M. W.;
Chen, Y.; Struthers, R. S.; Xie, Q.; Saunders, J.; Reinhart,
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Chem. 2004, 47, 1259.
Compared to 3f, the b-ethyl analog 3g (Ki = 3.7 nM) was
about 12-fold less potent, while the b-hydroxymethyl 3h
(K i = 0.7 nM) displayed only slightly reduced binding
affinity. The R-configured 4a and 4d were significantly
less potent than their S-isomers 3a and 3d. In contrast,
the discrepancy between the two stereoisomers for the
b-ethyl compounds was small. Thus, 4g (Ki = 7.4 nM)
was only 2-fold less potent than 3g in binding affinity.
The functional antagonist activity of these compounds
was demonstrated in an IP3 assay (Table 3).25 Thus,
3f-II exhibited an IC50 of 1.5 nM. 3f-I also shown
dose-dependent inhibition in this assay, but with much
lower potency (IC50 = 385 nM).
In summary, several uracils were characterized as a no-
vel class of GnRH-R antagonists. These 5-aryl-6-meth-
yluracils existed as atropisomers at room temperature.
While the 2-fluoro-5-methoxyphenyluracils such as 3a
presented
a pair of interchangeable atropisomers
aR-3a and aS-3a, replacement of the 2-fluorine with a
chlorine produced thermally stable atropisomers, which
were separable by HPLC. It was found that the atrop-
isomer II was much more potent as a GnRH-R antago-
nist than isomer I, demonstrating a stereo-preference for
receptor interactions. The X-ray crystal structure of 3h-
II showed an aR-configuration of this active isomer. Re-
ports have shown that stable biphenyl atropisomers can
be synthesized using a chiral Suzuki coupling reaction.26
In addition to the classical separation of atropisomers
by chromatography, crystallization of atropisomers with
a chiral salt has been described recently.27 Thus, a ther-
mally stable atropisomer may be a viable alternative for
further development of nonpeptide GnRH antagonists.
18. 3-[(2S)-Cyclopentylaminopropyl]-1-(2,6-difluorobenzyl)-
6-methyl-5-(2- fluoro-3-methoxyphenyl)pyrimidin-2,4-dione
hydrochloride (3a): 1H NMR (CDCl3): 1.17 (s, 3H), 1.51 (br
s, 2H), 1.62(br s, 2H), 1.71(br s, 2H), 1.92(br s, 2H), 2.17 (s,
3H), 3.43 (m, 1H), 3.62 (m, 1H), 3.85 (s, 3H), 4.14 (m, 2H),
5.26 (s, 2H), 6.76 (m, 1H), 7.12 (m, 2H), 7.18 (d, J = 5.2 Hz,
1H), 7.19 (m, 1H), 7.42 (m, 1H); 19F NMR:ꢀ115.0 (m, 2F),
ꢀ135.4 (m, 1F); 13C NMR: 14.5 and 14.6, 17.5, 23.5 (2C),
28.8 and 28.9, 28.9, 38.6, 42.6, 59.1 and 50.3, 55.5, 55.9,
106.8 and 106.9, 111.9 (m, 2C), 112.1 (t, J = 17 Hz), 113.5,
115.2, 118.5, 122.2 (d, J = 13.6 Hz), 123.6, 124.0 (d,
J = 3.8 Hz), 130.1 (t, J = 10.7 Hz), 147.4 (d, J = 10.7 Hz),
References and notes
1. (a) Matsuo, H.; Baba, Y.; Nair, R. M.; Arimura, A.;
Schally, A. V. Biochem. Biophys. Res. Commun. 1971, 43,