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
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Takeda Pharmaceut Co Ltd, CMC Ctr, Yodogawa Ku, Osaka 5328686, JapanTakeda Pharmaceut Co Ltd, CMC Ctr, Yodogawa Ku, Osaka 5328686, Japan
Miwa, Kazuhiro
[1
]
Hitaka, Takenori
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Takeda Pharmaceut Co Ltd, Div Pharmaceut Res, Yodogawa Ku, Osaka 5328686, JapanTakeda Pharmaceut Co Ltd, CMC Ctr, Yodogawa Ku, Osaka 5328686, Japan
Hitaka, Takenori
[2
]
Imada, Takashi
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Takeda Pharmaceut Co Ltd, Div Pharmaceut Res, Tsukuba, Ibaraki 3004293, JapanTakeda Pharmaceut Co Ltd, CMC Ctr, Yodogawa Ku, Osaka 5328686, Japan
Imada, Takashi
[3
]
Sasaki, Satoshi
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Takeda Pharmaceut Co Ltd, Div Pharmaceut Res, Tsukuba, Ibaraki 3004293, JapanTakeda Pharmaceut Co Ltd, CMC Ctr, Yodogawa Ku, Osaka 5328686, Japan
Sasaki, Satoshi
[3
]
Yoshimatsu, Mie
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Takeda Pharmaceut Co Ltd, Div Pharmaceut Res, Yodogawa Ku, Osaka 5328686, JapanTakeda Pharmaceut Co Ltd, CMC Ctr, Yodogawa Ku, Osaka 5328686, Japan
Yoshimatsu, Mie
[2
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Kusaka, Masami
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Takeda Pharmaceut Co Ltd, CMC Ctr, Yodogawa Ku, Osaka 5328686, JapanTakeda Pharmaceut Co Ltd, CMC Ctr, Yodogawa Ku, Osaka 5328686, Japan
Kusaka, Masami
[1
]
Tanaka, Akira
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Takeda Pharmaceut Co Ltd, Div Pharmaceut Res, Tsukuba, Ibaraki 3004293, JapanTakeda Pharmaceut Co Ltd, CMC Ctr, Yodogawa Ku, Osaka 5328686, Japan
Tanaka, Akira
[3
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Nakata, Daisuke
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Takeda Pharmaceut Co Ltd, Div Pharmaceut Res, Tsukuba, Ibaraki 3004293, JapanTakeda Pharmaceut Co Ltd, CMC Ctr, Yodogawa Ku, Osaka 5328686, Japan
Nakata, Daisuke
[3
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Furuya, Shuichi
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Takeda Pharmaceut Co Ltd, Div Pharmaceut Res, Tsukuba, Ibaraki 3004293, JapanTakeda Pharmaceut Co Ltd, CMC Ctr, Yodogawa Ku, Osaka 5328686, Japan
Furuya, Shuichi
[3
]
Endo, Satoshi
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Takeda Pharmaceut Co Ltd, Div Pharmaceut Res, Yodogawa Ku, Osaka 5328686, JapanTakeda Pharmaceut Co Ltd, CMC Ctr, Yodogawa Ku, Osaka 5328686, Japan
Endo, Satoshi
[2
]
Hamamura, Kazumasa
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Takeda Pharmaceut Co Ltd, Div Pharmaceut Res, Yodogawa Ku, Osaka 5328686, JapanTakeda Pharmaceut Co Ltd, CMC Ctr, Yodogawa Ku, Osaka 5328686, Japan
Hamamura, Kazumasa
[2
]
Kitazaki, Tomoyuki
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Takeda Pharmaceut Co Ltd, Div Pharmaceut Res, Yodogawa Ku, Osaka 5328686, JapanTakeda Pharmaceut Co Ltd, CMC Ctr, Yodogawa Ku, Osaka 5328686, Japan
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
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.
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La Jolla Agouron Pharmaceut Inc, Pfizer Global Res & Dev, Res Pharmacol, San Diego, CA 92121 USALa Jolla Agouron Pharmaceut Inc, Pfizer Global Res & Dev, Res Pharmacol, San Diego, CA 92121 USA
Anderes, KL
;
Luthin, DR
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La Jolla Agouron Pharmaceut Inc, Pfizer Global Res & Dev, Res Pharmacol, San Diego, CA 92121 USALa Jolla Agouron Pharmaceut Inc, Pfizer Global Res & Dev, Res Pharmacol, San Diego, CA 92121 USA
Luthin, DR
;
Castillo, R
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La Jolla Agouron Pharmaceut Inc, Pfizer Global Res & Dev, Res Pharmacol, San Diego, CA 92121 USALa Jolla Agouron Pharmaceut Inc, Pfizer Global Res & Dev, Res Pharmacol, San Diego, CA 92121 USA
Castillo, R
;
Kraynov, EA
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La Jolla Agouron Pharmaceut Inc, Pfizer Global Res & Dev, Res Pharmacol, San Diego, CA 92121 USALa Jolla Agouron Pharmaceut Inc, Pfizer Global Res & Dev, Res Pharmacol, San Diego, CA 92121 USA
Kraynov, EA
;
Castro, M
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La Jolla Agouron Pharmaceut Inc, Pfizer Global Res & Dev, Res Pharmacol, San Diego, CA 92121 USALa Jolla Agouron Pharmaceut Inc, Pfizer Global Res & Dev, Res Pharmacol, San Diego, CA 92121 USA
Castro, M
;
Hood, KN
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La Jolla Agouron Pharmaceut Inc, Pfizer Global Res & Dev, Res Pharmacol, San Diego, CA 92121 USALa Jolla Agouron Pharmaceut Inc, Pfizer Global Res & Dev, Res Pharmacol, San Diego, CA 92121 USA
Hood, KN
;
Gregory, ML
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La Jolla Agouron Pharmaceut Inc, Pfizer Global Res & Dev, Res Pharmacol, San Diego, CA 92121 USALa Jolla Agouron Pharmaceut Inc, Pfizer Global Res & Dev, Res Pharmacol, San Diego, CA 92121 USA
Gregory, ML
;
Pathak, VP
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La Jolla Agouron Pharmaceut Inc, Pfizer Global Res & Dev, Res Pharmacol, San Diego, CA 92121 USALa Jolla Agouron Pharmaceut Inc, Pfizer Global Res & Dev, Res Pharmacol, San Diego, CA 92121 USA
Pathak, VP
;
Christie, LC
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La Jolla Agouron Pharmaceut Inc, Pfizer Global Res & Dev, Res Pharmacol, San Diego, CA 92121 USALa Jolla Agouron Pharmaceut Inc, Pfizer Global Res & Dev, Res Pharmacol, San Diego, CA 92121 USA
Christie, LC
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Paderes, G
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La Jolla Agouron Pharmaceut Inc, Pfizer Global Res & Dev, Res Pharmacol, San Diego, CA 92121 USALa Jolla Agouron Pharmaceut Inc, Pfizer Global Res & Dev, Res Pharmacol, San Diego, CA 92121 USA
Paderes, G
;
Vazir, H
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La Jolla Agouron Pharmaceut Inc, Pfizer Global Res & Dev, Res Pharmacol, San Diego, CA 92121 USALa Jolla Agouron Pharmaceut Inc, Pfizer Global Res & Dev, Res Pharmacol, San Diego, CA 92121 USA
Vazir, H
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Ye, Q
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La Jolla Agouron Pharmaceut Inc, Pfizer Global Res & Dev, Res Pharmacol, San Diego, CA 92121 USALa Jolla Agouron Pharmaceut Inc, Pfizer Global Res & Dev, Res Pharmacol, San Diego, CA 92121 USA
Ye, Q
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Anderson, MB
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La Jolla Agouron Pharmaceut Inc, Pfizer Global Res & Dev, Res Pharmacol, San Diego, CA 92121 USALa Jolla Agouron Pharmaceut Inc, Pfizer Global Res & Dev, Res Pharmacol, San Diego, CA 92121 USA
Anderson, MB
;
May, JM
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La Jolla Agouron Pharmaceut Inc, Pfizer Global Res & Dev, Res Pharmacol, San Diego, CA 92121 USALa Jolla Agouron Pharmaceut Inc, Pfizer Global Res & Dev, Res Pharmacol, San Diego, CA 92121 USA
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La Jolla Agouron Pharmaceut Inc, Pfizer Global Res & Dev, Res Pharmacol, San Diego, CA 92121 USALa Jolla Agouron Pharmaceut Inc, Pfizer Global Res & Dev, Res Pharmacol, San Diego, CA 92121 USA
Anderes, KL
;
Luthin, DR
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La Jolla Agouron Pharmaceut Inc, Pfizer Global Res & Dev, Res Pharmacol, San Diego, CA 92121 USALa Jolla Agouron Pharmaceut Inc, Pfizer Global Res & Dev, Res Pharmacol, San Diego, CA 92121 USA
Luthin, DR
;
Castillo, R
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La Jolla Agouron Pharmaceut Inc, Pfizer Global Res & Dev, Res Pharmacol, San Diego, CA 92121 USALa Jolla Agouron Pharmaceut Inc, Pfizer Global Res & Dev, Res Pharmacol, San Diego, CA 92121 USA
Castillo, R
;
Kraynov, EA
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La Jolla Agouron Pharmaceut Inc, Pfizer Global Res & Dev, Res Pharmacol, San Diego, CA 92121 USALa Jolla Agouron Pharmaceut Inc, Pfizer Global Res & Dev, Res Pharmacol, San Diego, CA 92121 USA
Kraynov, EA
;
Castro, M
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La Jolla Agouron Pharmaceut Inc, Pfizer Global Res & Dev, Res Pharmacol, San Diego, CA 92121 USALa Jolla Agouron Pharmaceut Inc, Pfizer Global Res & Dev, Res Pharmacol, San Diego, CA 92121 USA
Castro, M
;
Hood, KN
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La Jolla Agouron Pharmaceut Inc, Pfizer Global Res & Dev, Res Pharmacol, San Diego, CA 92121 USALa Jolla Agouron Pharmaceut Inc, Pfizer Global Res & Dev, Res Pharmacol, San Diego, CA 92121 USA
Hood, KN
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Gregory, ML
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La Jolla Agouron Pharmaceut Inc, Pfizer Global Res & Dev, Res Pharmacol, San Diego, CA 92121 USALa Jolla Agouron Pharmaceut Inc, Pfizer Global Res & Dev, Res Pharmacol, San Diego, CA 92121 USA
Gregory, ML
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Pathak, VP
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La Jolla Agouron Pharmaceut Inc, Pfizer Global Res & Dev, Res Pharmacol, San Diego, CA 92121 USALa Jolla Agouron Pharmaceut Inc, Pfizer Global Res & Dev, Res Pharmacol, San Diego, CA 92121 USA
Pathak, VP
;
Christie, LC
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La Jolla Agouron Pharmaceut Inc, Pfizer Global Res & Dev, Res Pharmacol, San Diego, CA 92121 USALa Jolla Agouron Pharmaceut Inc, Pfizer Global Res & Dev, Res Pharmacol, San Diego, CA 92121 USA
Christie, LC
;
Paderes, G
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La Jolla Agouron Pharmaceut Inc, Pfizer Global Res & Dev, Res Pharmacol, San Diego, CA 92121 USALa Jolla Agouron Pharmaceut Inc, Pfizer Global Res & Dev, Res Pharmacol, San Diego, CA 92121 USA
Paderes, G
;
Vazir, H
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La Jolla Agouron Pharmaceut Inc, Pfizer Global Res & Dev, Res Pharmacol, San Diego, CA 92121 USALa Jolla Agouron Pharmaceut Inc, Pfizer Global Res & Dev, Res Pharmacol, San Diego, CA 92121 USA
Vazir, H
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Ye, Q
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La Jolla Agouron Pharmaceut Inc, Pfizer Global Res & Dev, Res Pharmacol, San Diego, CA 92121 USALa Jolla Agouron Pharmaceut Inc, Pfizer Global Res & Dev, Res Pharmacol, San Diego, CA 92121 USA
Ye, Q
;
Anderson, MB
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La Jolla Agouron Pharmaceut Inc, Pfizer Global Res & Dev, Res Pharmacol, San Diego, CA 92121 USALa Jolla Agouron Pharmaceut Inc, Pfizer Global Res & Dev, Res Pharmacol, San Diego, CA 92121 USA
Anderson, MB
;
May, JM
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La Jolla Agouron Pharmaceut Inc, Pfizer Global Res & Dev, Res Pharmacol, San Diego, CA 92121 USALa Jolla Agouron Pharmaceut Inc, Pfizer Global Res & Dev, Res Pharmacol, San Diego, CA 92121 USA