3486 J ournal of Medicinal Chemistry, 2004, Vol. 47, No. 14
Letters
tagonists. Bioorg. Med. Chem. Lett. 2002, 12, 339-402. (b) Zhu,
Y.-F.; Wilcoxen, K.; Saunders, J .; Guo, Z.; Gao, Y.; Connors, P.
J ., J r.; Gross, T. D.; Tucci, F. C.; Struthers, R. S.; Reinhart, G.
J .; Xie, Q.; Chen, C. A Novel Synthesis of 2-Arylpyrrolo[1,2-a]-
pyrimid-7-ones and Their Structure-Activity Relationships as
Potent GnRH Receptor Antagonists. Bioorg. Med. Chem. Lett.
2002, 12, 403-406. (c) Wilcoxen, K.; Zhu, Y.-F.; Connors, P. J .,
J r.; Saunders, J .; Gross, T. D.; Gao, Y.; Reinhart, G. J .; Struthers,
R. S.; Chen, C. Synthesis and Initial Structure-Activity Rela-
tionships of a Novel Series of Imidazolo[1,2-a]pyrimid-4-ones as
Potent GnRH receptor antagonists. Bioorg. Med. Chem. Lett.
2002, 12, 2179-2184. (d) Gross, T. D.; Zhu, Y.-F.; Saunders, J .;
Gao, Y.; Connors, P. J ., J r.; Guo, Z.; Struthers, R. S.; Reinhart,
G. J .; Chen, C. Synthesis and Structure-Activity Relationships
of a Novel Series of Imidazolo[1,2-a]pyrimid-4-ones as Potent
GnRH Receptor Antagonist. Bioorg. Med. Chem. Lett. 2002, 12,
2185-2187. (e) Tucci, F. C.; Zhu, Y.-F.; Guo, Z.; Gross, T. D.;
Connors, P. J ., J r.; Struthers, R. S.; Reinhart, G. J .; Wang, X.;
Saunders, J .; Chen, C. A Novel Synthesis of 7-Aryl-8-fluoro-
pyrrolo[1,2-a]pyrimid-4-ones as Potent, Stable GnRH Receptor
Antagonists. Bioorg. Med. Chem. Lett. 2002, 12, 3491-3495. (f)
Zhu, Y.-F.; Guo, Z.; Gross, T. D.; Gao, Y.; Connors, P. J .;
Struthers, R. S.; Xie, Q.; Tucci, F. C.; Reinhart, G. J .; Wu, D.;
Saunders, J .; Chen, C. Design and Structure-Activity Relation-
ships of 2-Alkyl-3-aminomethyl-6-(3-methoxyphenyl)-7-methyl-
8-(2-fluorobenzyl)imidazolo[1,2-a]pyrimid-5-ones as Potent GnRH
Receptor Antagonists. J . Med. Chem. 2003, 46, 1769-1772. (g)
Zhu, Y.-F.; Gross, T. D.; Guo, Z.; Connors, P. J ., J r.; Gao, Y.;
Tucci, F. C.; Struthers, R. S.; Reinhart, G. J .; Saunders, J .; Chen,
T. K.; Bonneville, A. L. K.; Chen, C. Identification of 1-Aryl-
methyl-3-(2-aminoethyl)-5-aryluracil as Novel Gonadotropin-
Releasing Hormone Receptor Antagonists. J . Med. Chem. 2003,
46, 2023-2026. (h) Guo, Z.; Zhu, Y.-F.; Tucci, F. C.; Gao, Y.;
Struthers, R. S.; Saunders, J .; Gross, T. D.; Xie, Q.; Reinhart,
G. J .; Chen, C. Synthesis and Structure-Activity Relationships
of 1-Arylmethyl-3-(2-aminopropyl)-5-aryl-6-methyluracils as Po-
tent GnRH Receptor Antagonists. Bioorg. Med. Chem. Lett. 2003,
13, 3311-3315. (i) Tucci, F. C.; Zhu, Y.-F.; Guo, Z.; Gross, T. D.;
Connors, P. J ., J r.; Struthers, R. S.; Reinhart, G. J .; Saunders,
J .; Chen C. Synthesis and Structure-Activity Relationships
of 1-Arylmethyl-3-(1-methyl-2-amino)ethyl-5-aryl-6-methylura-
cils as Antagonists of the Human GnRH Receptor. Bioorg. Med.
Chem. Lett. 2003, 13, 3317-3322. (j) Guo, Z.; Zhu, Y.-F.; Gross,
T. D.; Tucci, F. C.; Gao, Y.; Moorjani, M.; Connors, P. J ., J r.;
Rowbottom, M. R.; Chen, Y.; Struthers, R. S.; Xie, Q.; Saunders,
J .; Reinhart, G. J .; Chen, T. K.; Bonneville, A. L. K.; Chen, C.
Synthesis and Structure-Activity Relationships of 1-Arylmethyl-
5-aryl-6-methyluracils as Potent Gonadotropin-Releasing Hor-
mone Receptor Antagonists. J . Med. Chem. 2004, 47, 1259-
1271.
(4) For leading references, see the following. (a) Sasaki, S.; Cho,
N.; Nara, Y.; Harada, M.; Endo, S.; Suzuki, N.; Furuya, S.;
Fujino, M. Discovery of a Thieno[2,3-d]pyrimidine-2,4-dione
Bearing a p-Methoxyureidophenyl Moiety at the 6-Position: A
Highly Potent and Orally Bioavailable Non-Peptide Antagonist
for the Human Luteinizing Hormone-Releasing Hormone Recep-
tor. J . Med. Chem. 2003, 46, 113-124. (b) DeVita, R. J .; Walsh,
T. F.; Young, J . R.; J iang, J .; Ujjainwalla, F.; Toupence, R. B.;
Parikh, M.; Huang, S. X.; Fair, J . A.; Goulet, M. T.; Wyvratt, M.
J ., J r.; Lo, J .-L.; Ren, N.; Yudkovitz, J . B.; Yang, Y. T.; Cheng,
K.; Cui, J .; Mount, G.; Rohrer, S. P.; Schaeffer, J . M.; Rhodes,
L.; Drisko, J . E.; McGowan, E.; MacIntyre, D. E.; Vincent, S.;
Carlin, J . R.; Cameron, J .; Smith, R. G. A Potent, Nonpeptidyl
1H-Quinolone Antagonist for the Gonadotropin-Releasing Hor-
mone Receptor. J . Med. Chem. 2001, 44, 917-922. (c) Young, J .
R.; Huang, S. X.; Walsh, T. F.; Wyvratt, M. J ., J r.; Yang, Y. T.;
Yudkovitz, J . B.; Cui, J .; Mount, G. R.; Ren, R. N.; Wu, T.-J .;
Shen, X.; Lyons, K. A.; Mao, A.-H.; Carlin, J . R.; Karanam, B.
V.; Vincent, S. H.; Cheng, K.; Goulet, M. 2-Arylindoles as
Gonadotropin Releasing Hormone (GnRH) Antagonists: Opti-
mization of the Tryptamine Side Chain. Bioorg. Med. Chem. Lett.
2002, 12, 827-832. (d) Luthin, D. R.; Hong, Y.; Tompkins, E.;
Anderes, K. L.; Paderes, G.; Kraynov, E. A.; Castro, M. A.;
Nared-Hood, K. D.; Castillo, R.; Gregory, M.; Vazir, H.; May, J .
M.; Anderson, M. B. Characterization of Mono- and Diaminopy-
rimidine Derivatives as Novel, Nonpeptide Gonadotropin Re-
leasing Hormone (GnRH) Receptor Antagonists. Bioorg. Med.
Chem. Lett. 2002, 12, 3635-3639.
(5) Perrin, M. H.; Haas, Y.; Rivier, J . E.; Vale, W. W. Mol Pharmacol.
1983, 23, 44. For experimental procedures detailing the binding
assay, please refer to the Supporting Information.
(6) On each assay plate a standard antagonist of affinity comparable
to those being tested was included as a control for plate-to-plate
variability. All compounds were assayed in three to eight
independent experiments.
(7) For experimental details of the hGnRH functional assay, please
refer to the Supporting Information.
J M049791W