Discovery of 1-{4[1-(2,6-Difluorobenzyl)-5-[(dimethylamino)methyl]-3-(6-methoxypyridazin-3-yl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl]phenyl]-3-methoxyurea (TAK-385) as a Potent, Orally Active, Non-Peptide Antagonist of the Human Gonadotropin-Releasing Hormone Receptor

被引:93
作者
Miwa, Kazuhiro [1 ]
Hitaka, Takenori [2 ]
Imada, Takashi [3 ]
Sasaki, Satoshi [3 ]
Yoshimatsu, Mie [2 ]
Kusaka, Masami [1 ]
Tanaka, Akira [3 ]
Nakata, Daisuke [3 ]
Furuya, Shuichi [3 ]
Endo, Satoshi [2 ]
Hamamura, Kazumasa [2 ]
Kitazaki, Tomoyuki [2 ]
机构
[1] Takeda Pharmaceut Co Ltd, CMC Ctr, Yodogawa Ku, Osaka 5328686, Japan
[2] Takeda Pharmaceut Co Ltd, Div Pharmaceut Res, Yodogawa Ku, Osaka 5328686, Japan
[3] Takeda Pharmaceut Co Ltd, Div Pharmaceut Res, Tsukuba, Ibaraki 3004293, Japan
关键词
HUMAN GNRH RECEPTOR; LHRH ANTAGONISTS; SUBSTITUTED INDOLE-5-CARBOXAMIDES; BENZIMIDAZOLE DERIVATIVES; ERYTHROMYCIN-A; SIDE-CHAIN; DESIGN; IDENTIFICATION; AGONISTS; 2-ARYLINDOLES;
D O I
10.1021/jm200216q
中图分类号
R914 [药物化学];
学科分类号
100701 ;
摘要
We previously discovered an orally active human gonadotropin-releasing hormone (GnRH) receptor antagonist, thieno[2,3-d] Pyrimidine-2,4-dione derivative 1 (sufugolix). To reduce the cytochrome P450 (CYP) inhibitory activity and improve in vivo GnRH antagonistic activity, further optimization of this scaffold was carried out. We focused our synthetic efforts on chemical modification at the 5 and 3 positions of the thieno[2,3-d]pyrimidine-2,4-dione ring based on computational modeling, which resulted in the discovery of 1-{4-[1-(2,6-difluorobenzyl)-5-[(dimethylamino)methyl]-3-(6-methoxypyridazin-3-yl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl]phenyl}-3-methoxyurea (161)) as a highly potent and orally active GnRH antagonist. Compound 16b showed potent in vitro GnRH antagonistic activity in the presence of fetal bovine serum (FBS) without CYP inhibition. Oral administration of 16b maintained the suppressive effect of the plasma luteinizing hormone levels in castrated cynomolgus monkeys at a 3 mg/kg dose for more than 24 h. Compound 16b is currently under clinical development with the Code name of TAK-385.
引用
收藏
页码:4998 / 5012
页数:15
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